Marin Cilic became the first seed to fall at the 2011 French Open after a surprise 7-6 (7-5) 6-4 6-4 defeat by Spain's Ruben Ramirez Hidalgo.
The Croatian 19th seed made 67 unforced errors as his 33-year-old opponent reached round two of a Grand Slam for only the second time in 13 attempts.
There was better news for seventh seed David Ferrer as he overcame Finland's Jarkko Nieminen 6-3 6-3 6-1.
Stanislas Wawrinka and Jo-Wilfried Tsonga were also victorious.
Wawrinka, seeded 14th, bounced back from losing the first set to eliminate Frenchman Augustin Gensse with a 4-6 6-3 6-4 6-2 win.
"I don't know if relieved is the right word; I'm happy, I'm satisfied," said Wawrinka, who could meet Swiss compatriot Roger Federer in the last 16.
"I expected, like every year, the first match not to be too easy. He played really well. I was a bit slow. I took some time before I got into the match.
"But I felt better at the end and I'm glad I won in four sets."
Next up for Wawrinka is Maximo Gonzalez or Thomas Schoorel while French 17th seed Tsonga, who beat Jan Hajek 6-3 6-2 6-2, plays Florent Serra or Igor Andreev.
"I was relatively relaxed and I started the match really well," stated Tsonga. "I dominated him throughout.
"It was not obvious because of the gusts of wind. It was not my best type of tennis but, given the conditions, it was not bad."
Ferrer has been one of the most successful players on clay this season, reaching finals in Monte Carlo and Barcelona, and he proved far too strong for Nieminen.
The Spaniard, a two-time French Open quarter-finalist, will face Julien Benneteau for a place in round three after he ousted Rui Machado in four sets.
"I always hope I get good performances in Paris," commented Ferrer. "I think you need to take it step by step, one match after the other, because all matches are different."
Cilic has endured a frustrating campaign and losing to Ramirez Hidalgo will see him fall from his current world ranking of 20th.
The Croat looked set to become a fixture in the top 10 when he reached the 2010 Australian Open semi-finals, but he has since struggled to impose himself at any of the major tournaments.
Cilic reached round four at the French Open in 2009 and 2010, and this is his earliest exit in Paris since 2007.
Ramirez Hidalgo, who got to the fourth round at Roland Garros in 2006, next faces compatriot Albert Montanes, a 6-4 6-4 6-2 victor over Marc Gicquel.
"The truth is that when I saw the draw, it wasn't very good for me, but I knew that with a little luck I'd win," said Ramirez Hidalgo.
Another Spaniard to advance was 30th seed Guillermo Garcia-Lopez and he will take on Tommy Haas or Marsel Ilhan after a 6-1 7-5 4-6 6-3 triumph over Robert Kendrick of the United States.
Elsewhere, 31st seed Sergiy Stakhovsky of Ukraine came from a set down to beat French qualifier David Guez 6-7 (7-9) 6-3 6-3 6-3.
That set up a second-round encounter with Japan's Kei Nishikori, a 6-1 6-3 6-4 winner against Lu Yen-Hsun of Taiwan.
"I started well but he played better in the second set and by the third he was hitting well, side-to-side and was more aggressive," said Nishikori. "But, overall, I played a pretty solid match.
"I was close to not playing [the French Open]. My stomach had been hurting, but I started to feel better so I decided to come.
"Physically and tennis-wise, it's pretty good and I'm confident."
It was a far less satisfying day for Latvia's Ernests Gulbis as the former world number 21 lost 6-1 6-4 6-1 Blaz Kavcic of Slovenia.
Gulbis has now suffered first-round defeats at each of his last six Grand Slam tournaments and has not made it passed round two since Wimbledon 2008.