Seven-time winner Roger Federer lost in straight sets to 21-year-old Russian qualifier Andrey Rublev in the third round of the Cincinnati Masters.
The world number 70 won 6-3 6-4 in just over an hour to set up a quarter-final against compatriot Daniil Medvedev.
Swiss 20-time Grand Slam champion Federer, ranked third, plans to compete at the US Open later this month.
Defeat means he will have played just two matches in preparation, after an opening win over Juan Ignacio Londero.
On Rublev, Federer said: "He was excellent today. He didn't give me anything. It was tough for me but an excellent match for him.