Pietersen was dropped on one but went on to hammer 53 from 39 balls, including a huge switch-hit six.
Earlier, Steven Finn took 3-22 and Ravi Bopara grabbed two wickets as India were restricted to 120-9 in Kolkata.
After Pietersen passed a fitness test to be named in the side, England lost the toss and fielded first, eager to return to winning ways after their 5-0 hiding in the one day series.
Finn, England's outstanding performer in India, opened the bowling and struck after only three balls as Ajinkya Rahane edged behind and Craig Kieswetter took a fine catch.
The wicketkeeper was at full stretch but took the ball right at the top of his gloves, and took a second catch an over later as Tim Bresnan drew Robin Uthappa into a loose shot.
Suresh Raina kept the scoreboard ticking over, hoisting England captain Graeme Swann for a big six to bring up India's 50 in the eighth over, but two wickets in two balls from the excellent Finn left India at 74-6.
Test Match Special analysis
Matthew HoggardFormer England seamer & TMS pundit
Pietersen showed what a class act he is and why he should be in the team. He was the difference between the teams. It's a good effort to come out and play with a broken thumb and to come out as positively as he did and dominate the bowling was good to see. It's nice to be on the winning side after being on the losing side so much
When Ravi Bopara bowled Yusuf Pathan and Praveen Kumar with some reverse swing, it was left to India captain Mahendra Dhoni to add some much-needed impetus to the innings.
Dhoni hit a six off Jade Dernbach in the final over but was run out off the last ball of the innings for a disappointing 21 as India posted 120.
It was the first time the India captain had been dismissed during England's tour.
England openers Craig Kieswetter and Alex Hales made a brisk response before Kieswetter was caught by Manoj Tiwary after miscuing Ravindra Jadeja high into the air.
That brought Pietersen to the crease, and he should have been dismissed on one when he chipped the ball up, but Raina dropped the regulation chance and Pietersen soon set about making India pay.
England's next fixtures
January 17-21 2012 - First Test v Pakistan (in Dubai)
January 25-29 - Second Test (Abu Dhabi)
February 3-7 - Third Test (Dubai)
He hit a four with a 'Dilscoop' over wicketkeeper Dhoni's head and then hit the shot of the match with a huge switch-hit six.
Hales was caught on the fence by Rahane off Yusuf Pathan but Samit Patel - promoted up the order to come in at four - kept Pietersen company with a flurry of fine shots of his own.
Pietersen went past 50 but was finally dismissed lbw by Raina to a ball that looked as if it pitched outside leg stump.
He was later issued with an official reprimand by the International Cricket Council for showing dissent following the decision.
Patel was out when he chipped Virat Kohli to cover but Bopara was able to steer the winning run with eight balls remaining to keep England at number one in the Twenty20 world rankings.
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