Nani scored one goal and created another for Javier Hernandez to take Manchester United past Reading and into the FA Cup quarter-finals.
The Portuguese winger, on as a first-half substitute for the injured Phil Jones, struck the opener from Antonio Valencia's pass.
He then crossed for Hernandez to head past keeper Adam Federici.
Jobi McAnuff pulled one back, but United held on to set up a home tie against Middlesbrough or Chelsea.
Manchester United were facing Premier League opposition for the seventh FA Cup tie in a row. It was their 22nd pairing with top-flight opposition in their last 27 FA Cup ties.
The loss of Jones, who limped off with an injury to his right ankle after a first-half challenge on McAnuff, will be a concern to United manager Sir Alex Ferguson.
And the Premier League leaders made heavy work of beating a spirited Reading side before securing the victory that took them into the last eight.
Ferguson made eight changes to the side which earned a 1-1 away draw against Real Madrid in their Champions League last-16 first-leg match last Wednesday, with only David de Gea, Jones and Danny Welbeck retaining their places.
Reading manager Brian McDermott, meanwhile, made six changes, giving in-form striker Adam Le Fondre a chance in the starting line-up.
United made most of the chances in the opening 45 minutes, and looked as if they might overwhelm McDermott's side with an early burst of pressure, but the visitors defended solidly and Federici was only rarely called into action.
The keeper reacted well to stop Welbeck's early drive, moments after the United striker and team-mate Valencia had been unable to turn home a loose ball when Hernandez had a shot blocked.
Federici made a terrific double save midway through the first half, pushing aside Tom Cleverley's 20-yard drive and then recovering to turn Ashley Young's follow-up around the post.
Reading striker Noel Hunt had to change his shirt twice after an early aerial collision with defender Nemanja Vidic that left both men bleeding, and needed additional treatment at half-time.
The visitors rarely threatened in the first half, although McAnuff had a penalty appeal rejected after claiming he was fouled by Jones as he tried to drive into the United penalty area.
Sir Alex Ferguson's side have won their last six FA Cup ties at Old Trafford. They've lost to a fellow Premier League club on their own ground only once in nine years; 1-0 to Portsmouth in the sixth round in March 2008.
With the home side temporarily reduced to 10 men after Jones went off, Le Fondre turned on the edge of the penalty area and hit a shot that De Gea held.
But Reading had two escapes at the end of the first half, when Nani struck the post with an excellent volley, and then hit a left-foot strike from the edge of the penalty area that Federici did well to push aside.
United continued to press in the second half, with Hunt clearing a deflected Vidic header off the line, before Federici saved from Anderson and Nani flashed a shot wide.
Ferguson's obvious frustration at the visitors slowing the game down extended to a message apparently being sent to the ball-boys to do their jobs with a little more speed.
But United finally broke through when Nani collected Valencia's pass and drove the ball into the corner of the net.
De Gea denied Le Fondre an instant equaliser with a smart save, before Hernandez evaded Reading centre-back Sean Morrison to head in Nani's cross.
But McAnuff set up a nervous finale for United when he wriggled through to slot the ball home and give McDermott's side hope.
Le Fondre almost equalised in a frantic finish, with Hernandez denied by Federici at the other end, as United saw the game through.
Manchester United manager Sir Alex Ferguson:
"The last 10 minutes were a bit scary.
"Some of the football tonight was fantastic and we could have scored a lot of goals. In that way I'm satisfied.
"We didn't want a replay though and, in fairness, we dug in and defended the long throw-ins and the balls into the box.
"You cannot get any better than a home tie in the Cup. It doesn't matter who we play, at Old Trafford we have got a chance."
Reading manager Brian McDermott:
"We gave them a real run for their money.
"It makes you think when they can bring on players like Robin van Persie as well. When he was warming up I told him to sit down.
"We have to come back here in the league and will know a bit more about what to expect.
"We really wanted to put on a performance for our fans and we have done that. Now we can look forward to Saturday's game against Wigan."
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Live Text Commentary
Full Time The referee brings the game to a close.90:00 +4:17
Effort on goal by Javier Hernandez from 20 yards. Save by Adam Federici. Foul by Jem Karacan on Luis Nani, free kick awarded. Direct strike on goal from the free kick comes in from Luis Nani.90:00 +3:37
Inswinging corner taken from the right by-line by Nicky Shorey.90:00 +2:32
Luis Nani challenges Jem Karacan unfairly and gives away a free kick. Free kick crossed left-footed by Nicky Shorey, clearance by Chris Smalling.90:00 +0:13
Short corner worked by Luis Nani.87:04
Javier Hernandez produces a drilled right-footed shot from 20 yards. Save by Adam Federici. Luis Nani has an effort at goal from deep inside the area missing to the right of the target.83:41
The ball is crossed by Stephen Kelly, clearance made by Nemanja Vidic. Danny Guthrie takes a shot. Blocked by Chris Smalling.82:29 Substitution
Substitution Michael Carrick comes on in place of Oliveira Anderson.82:29
Jobi McAnuff produces a cross, Nemanja Vidic manages to make a clearance. Shot on goal by Stephen Kelly from just inside the area clears the crossbar.80:28 Goal scored
Goal! - Jobi McAnuff - Man Utd 2 - 1 Reading Jobi McAnuff grabs a goal from inside the penalty area to the bottom left corner of the goal. Man Utd 2-1 Reading.80:02
Shot from 20 yards from Jobi McAnuff. Chris Smalling gets a block in. Hal Robson-Kanu takes a shot. Blocked by Nemanja Vidic.77:20
The ball is swung over by Nicky Shorey.73:35
Javier Hernandez takes a shot. Adrian Mariappa gets a block in. The referee penalises Antonio Valencia for handball. Direct free kick taken by Adam Federici.73:15
Jem Karacan sends in a cross, save made by David De Gea.71:15
Assist on the goal came from Luis Nani.71:15 Goal scored
Goal! - Javier Hernandez - Man Utd 2 - 0 Reading Javier Hernandez scores a headed goal from inside the six-yard box. Man Utd 2-0 Reading.70:33
Drilled left-footed shot by Adam Le Fondre. Brilliant save by David De Gea. The assistant referee flags for offside against Noel Hunt. Free kick taken by David De Gea.69:03 Substitution
Substitution Garath McCleary leaves the field to be replaced by Hal Robson-Kanu.68:42
Assist on the goal came from Antonio Valencia.68:42 Goal scored
Goal! - Luis Nani - Man Utd 1 - 0 Reading Luis Nani gets on the score sheet with a goal from inside the box to the bottom left corner of the goal. Man Utd 1-0 Reading.
The ball is delivered by Luis Nani, save by Adam Federici.67:46
Robin van Persie takes a shot. Blocked by Sean Morrison.66:36
Luis Nani sends in a cross, blocked by Nicky Shorey. Corner taken left-footed by Robin van Persie from the right by-line, Stephen Kelly manages to make a clearance.64:56
Luis Nani has an effort at goal from outside the box which goes wide left of the goal.64:43
Tom Cleverley crosses the ball, clearance made by Sean Morrison.62:06 Substitution
Substitution Robin van Persie on for Ashley Young.62:06 Substitution
Substitution Danny Guthrie joins the action as a substitute, replacing Mikele Leigertwood.62:06
Tom Cleverley crosses the ball, clearance by Stephen Kelly. Outswinging corner taken by Ashley Young, Luis Nani has an effort at goal from just inside the box that misses to the right of the target.61:16
The assistant referee signals for offside against Noel Hunt. Free kick taken by David De Gea.59:56
Oliveira Anderson takes a shot. Save made by Adam Federici. Short corner worked by Oliveira Anderson. Luis Nani crosses the ball, Sean Morrison manages to make a clearance.59:28
Garath McCleary takes a shot. Oliveira Anderson gets a block in.56:56
Corner taken by Ashley Young. Outswinging corner taken right-footed by Ashley Young from the right by-line, Nemanja Vidic takes a shot. Blocked by Sean Morrison.54:23
Free kick taken by Chris Smalling.54:23 Booking
Booking The referee cautions Noel Hunt for unsporting behaviour.54:16
Noel Hunt gives away a free kick for an unfair challenge on Chris Smalling.53:23
Noel Hunt challenges Danny Welbeck unfairly and gives away a free kick. Chris Smalling restarts play with the free kick.52:15
Jem Karacan challenges Ashley Young unfairly and gives away a free kick. Alexander Buttner takes the free kick.50:18
Luis Nani takes the chance to get an effort at goal. Save made by Adam Federici.49:23
Tom Cleverley takes a shot. Sean Morrison gets a block in. Inswinging corner taken by Oliveira Anderson from the right by-line, Stephen Kelly manages to make a clearance.46:45
The referee blows for offside. Nicky Shorey restarts play with the free kick.45:09
Unfair challenge on Ashley Young by Stephen Kelly results in a free kick. Alexander Buttner takes the direct free kick.45:01
The referee blows his whistle to start the second half.45:00 +4:30 Half time
Half Time The first half comes to an end.45:00 +3:18
Drilled left-footed shot by Luis Nani. Save by Adam Federici. Outswinging corner taken from the right by-line by Ashley Young, Tom Cleverley produces a right-footed shot from just outside the penalty box that goes wide left of the target.45:00 +1:36
Effort on goal by Garath McCleary from just inside the penalty area goes over the target.44:46
Danny Welbeck delivers the ball, clearance made by Sean Morrison. Luis Nani has an effort at goal from the edge of the area striking the post.44:03
Shot by Adam Le Fondre from 25 yards. Comfortable save by David De Gea.43:18
Luis Nani challenges Mikele Leigertwood unfairly and gives away a free kick. Free kick taken by Sean Morrison.42:53
Alexander Buttner produces a cross, Sean Morrison manages to make a clearance.41:47 Substitution
Substitution Luis Nani is brought on as a substitute for Phil Jones.41:47
Effort from outside the penalty box by Sean Morrison goes wide left of the target.41:16
Garath McCleary crosses the ball, clearance made by Antonio Valencia.40:27
Adam Le Fondre takes a shot. Blocked by Nemanja Vidic.34:28
Phil Jones fouled by Jobi McAnuff, the ref awards a free kick. Oliveira Anderson takes the direct free kick. Foul by Tom Cleverley on Jem Karacan, free kick awarded. Free kick taken by Nicky Shorey.32:39
Tom Cleverley takes a shot. Adrian Mariappa gets a block in. Inswinging corner taken left-footed by Oliveira Anderson from the right by-line, Headed effort from inside the area by Chris Smalling misses to the right of the target.28:59
Effort on goal by Garath McCleary from outside the penalty box goes harmlessly over the bar.27:32
Corner taken left-footed by Nicky Shorey, clearance made by Tom Cleverley.24:19
Javier Hernandez fouled by Jem Karacan, the ref awards a free kick. Free kick taken by Chris Smalling.22:44
Centre by Alexander Buttner, Adam Federici makes a comfortable save.21:42
Tom Cleverley produces a drilled right-footed shot from 25 yards. Save by Adam Federici. Ashley Young takes a shot. Adam Federici makes a save. Corner taken short by Ashley Young.19:35
Alexander Buttner sends in a cross.17:00
Unfair challenge on Noel Hunt by Nemanja Vidic results in a free kick. Nicky Shorey delivers the ball from the free kick left-footed from right wing, clearance made by Chris Smalling. Free kick awarded for an unfair challenge on Sean Morrison by Javier Hernandez. Direct free kick taken by Sean Morrison.16:03
Jobi McAnuff crosses the ball. Unfair challenge on Alexander Buttner by Garath McCleary results in a free kick. Alexander Buttner restarts play with the free kick.13:50
Ashley Young concedes a free kick for a foul on Stephen Kelly. Direct free kick taken by Sean Morrison.10:44
The ball is sent over by Phil Jones, save by Adam Federici.9:51
The referee blows for offside. Indirect free kick taken by Adam Federici.8:49
The ball is delivered by Jobi McAnuff, clearance made by Phil Jones.7:50
Inswinging corner taken by Nicky Shorey, clearance by Nemanja Vidic.4:45
Alexander Buttner fouled by Garath McCleary, the ref awards a free kick. Alexander Buttner takes the direct free kick.3:46
Ashley Young takes a shot. Stephen Kelly gets a block in.3:04
Danny Welbeck takes a shot. Save made by Adam Federici.2:31
The assistant referee signals for offside against Javier Hernandez. Adam Federici restarts play with the free kick.1:11
Javier Hernandez takes a shot. Blocked by Stephen Kelly. Danny Welbeck takes a shot. Adrian Mariappa gets a block in.0:00
The referee gets the game started.
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