Olympic champion Andy Murray was sent crashing out of the Cincinnati Masters, falling 6-4, 6-4 to French lucky loser Jeremy Chardy.
Britain's Murray won a match in Toronto last week before quitting with a knee injury but had looked impressive in his opener here against American Sam Querrey.
But the 25-year-old Murray was distinctly under-cooked against Chardy and his 16th unforced error of the second set sent the Frenchman into the last eight.
"This was like my second or third match in the hard court. I played well yesterday; didn't play so well today," said Murray on Thursday.
"Sometimes I've won tournaments in the buildup (to a major) and it hasn't helped me. That doesn't normally have that much bearing. But I would have liked to have done a bit better this week," he said, with the US Open on the horizon.
Four-time champion and top seed Roger Federer turned in another flawless performance, schooling Australian teenager Bernard Tomic 6-2, 6-4 with 27 winners.
"Overall I'm happy. But it's hard to judge my game in these quick conditions," said Federer, the Olympic silver medallist, who however admitted that his serve was "a bit off."
"It was a good performance, I'm playing as well as I want to right now," said the Swiss great.
Second seed Novak Djokovic barely broke a sweat against Nikolay Davydenko, who was nursing a shoulder injury and only lasted 30 minutes before quitting after Djokovic took the first set, 6-0.
Davydenko had 10 unforced errors and eight double-faults.
"This is not the way to win a match, it was clear that he was struggling physically," Djokovic said. "I just hope he will be fit for the US Open."
Canadian Milos Raonic upset fifth seed Tomas Berdych with 20 aces in a 6-4, 2-6, 6-2 win.
Olympic bronze medallist Juan Martin del Potro, who missed 2010 due to right wrist surgery, had troubles with his left wrist, but pushed through the pain to notch a 7-6 (7/2), 2-6, 6-1 win over Serbia's Viktor Troicki.
Tenth seed Mardy Fish continued to perform well on his home cement courts, beating Czech Radek Stepanek 6-3, 6-3 with seven aces and 23 winners. Fish will next play Federer.
Recent exertions in winning Wimbledon and Olympic gold caught up with Serena Williams, but the fatigued second seed nevertheless stumbled through into the WTA quarters. The 30-year-old defeated Urszula Radwanska 6-4, 6-3.
"I was tired out there," said Williams. "I just told myself to try to move my feet a bit, get through this match and go get some rest."
Top seed Agnieszka Radwanska beat American Sloane Stephens 6-1, 4-6, 6-4, while US Open titleholder Samantha Stosur beat Elena Makarova 6-1, 6-3.
Former Wimbledon winner Petra Kvitova, the fourth seed, advanced over China's Peng Shuai, 6-2, 6-2.
Andy Murray of Great Britain returns a shot to Jeremy Chardy of France during the Western & Southern Open at the Lindner Family Tennis Center. Murray was sent crashing out of the Cincinnati Masters on Thursday, going down to a shock 6-4, 6-4 defeat at the hands of Chardy.
Serena Williams serves against Urszula Radwanska of Poland during day six of the Western & Southern Open at Lindner Family Tennis Center. Williams scratched her way to a 6-4, 6-3 defeat of Radwanska.
Roger Federer waves to the crowd after defeating Bernard Tomic during day six of the Western & Southern Open at Lindner Family Tennis Center, on August 16, in Mason, Ohio. Federer won 6-2, 6-4.