Crashes by race leader Dani Pedrosa and championship leader Valentino Rossi left Jorge Lorenzo celebrating victory in the Red Bull Indianapolis MotoGP.
Lorenzo, winner of two of the first four races, crossed the winning line at the Brickyard 9.43 seconds clear of Alex De Angelis to put himself right back in contention for the championship.
His Yamaha team-mate Rossi failed to finish for the first time this season and saw his championship lead slashed to 25 points with five races to run.
"In the world championship if you want to win you have to be on the limit," said Lorenzo. "In the last two races I was on the limit, trying to win and I crashed, so it was a big disappointment.
"Today the situation has changed completely and now it has happened to Valentino and Dani – unfortunately for them.
It was certainly unfortunate for Honda rider Pedrosa, who had dominated practice and qualifying, only to crash on lap four while leading. The Spaniard rejoined the race and finished 10th.
Italian Rossi's inherited the lead, but only for five laps. He hit the ground while battling Lorenzo on lap nine. Rossi tried to carry on but had to retire two laps later. It’s the first time he has failed to complete a race since Valencia in 2007.
"Today is a disappointment of course. We struggled here with the setting all weekend but we made an improvement today and I got a good start and was able to stay in touch with Pedrosa ," said Rossi. "Once he fell, I knew it would be between Jorge and me but I honestly don't know how it would have finished because Jorge was very fast today.
"We are still leading the championship and this is the most important thing."
Nicky Hayden gave the home fans something to cheer by taking third on his Ducati to complete the podium.