You guys are all wrong. By far, the biggest upset had to be the 1989 Tour De France. France's own Laurent Fignon (RIP) is leading by 52 seconds in the final stage. Only time ever (since I was born, anyway, 1974) that it was a final stage TT to the Champs-Elysees. A 25 km stage, mostly flat/downhill. Everyone knew it was just a formality. Now, Greg Lemond uses that funny stuff from triathlons, aerobars, aero helmet. Fignon had his pony tail and an aero wheel. Greg Lemond had done a kickass job at the Giro's final stage, also a TT (50km). Some say he also had the same "iron injection" he had in Italy that day. Regardless, no one believed he had a chance, including me, watching it on TV, as the commentators where busy talking about Fignon's career and how he deserved it and how hard he worked. I never really liked Fignon and really liked Lemond, how had to struggle in French teams to be accepted in the peloton. He was coming back from being shot in that hunting accident, mind you.
Anyway, watching Lemond go and listening to the commentators continuing to ignore Lemond, it was shocking he was making up the time. At the end, Lemond's celebration was great, the stereotypical american yell ("Wooho/Yahoo") when he won was just as emotional as Fignon's collapse and cry. 8 seconds. He won by 8 seconds. Biggest upset ever. France was devastated as well. Never again will they do a final stage TT to the Champs-Elysses. The Giro has done it a few times since (loving the entrance to the Colosseum, btw) but France still feels the pain of Fignon.
TL;DR; Lemond beats Fignon.