Seven-time winner Roger Federer lost in the third round of the Cincinnati Masters in two sets against 21-year-old Russian qualifier Andrey Rublev.
The world number 70 won in just over an hour with 6: 3: 6: 4 and prevailed in the quarterfinals against compatriot Daniil Medvedev.
The Swiss 20-time Grand Slam champion Federer, who is in third place, wants to participate in the US Open this month.
A defeat means he has played only two games in preparation following an opening victory against Juan Ignacio Londero.
On Rublev, Federer said: "He was excellent today, he did not give me anything, it was tough for me but an excellent game for him, I was impressed.
"I just hoped for a better overall performance, he confused it well on the serve and on the return he was really consistent."
In a first meeting between the pair, Federer defeated 2-0 in the first set, but Rublev opened up a 4-1 lead from which the Swiss could not recover. He again had no answers when the Russian took the crucial break to go in the second game with 4: 3 in the lead.
After his biggest career success so far, Rublev said: "It's an incredible feeling to play a legend like Roger and all these people support him to the end, and one day I hope I'll feel the same way.
"Today I just tried to do my best and thought in my head that I have to play every point to the end, no matter what."