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The 23-year-old burst past Abel Kirui and Wilson Kipsang around the 38km mark to leave his two rivals trailing and claim only Uganda's second-ever Olympic gold in Athletics.
Kiprotich followed in the footsteps of his compatriot John Akii-Bua, who was 400m Hurdles champion 40 years ago, and crossed the line in 2:08.01.
Kirui took the silver, 26 seconds adrift, and long-time leader Kipsang finished with the bronze.
Kipsang, the London Marathon winner, made an early move to try to break up the lead group, building a 21-second lead at one point.
It was a high-risk strategy in such warm conditions, though, and he paid for it as the race went on as he started to look less and less comfortable.
He missed a drinks stop and by the 25km mark his advantage was down to seven seconds.
Kenyan world champion Kirui and Kiprotich soon joined the leader to make it a three-way battle for the gold medal.
Kiprotich looked to be starting to struggle, holding the back of his leg, but he suddenly produced a big surge, leapt to the front and pulled away.
And in front of packed crowds rows deep all along the looped central London course, the Ugandan, who moved to Kenya as a teenager to train, started smiling and pointing his finger into the air as he closed in on victory before draping himself in the Ugandan flag as he crossed the line.
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