Spain's Tommy Robredo shocked world number one Novak Djokovic 7-6(6) 7-5 on Thursday to move into the quarter-finals of the Western and Southern Open in Cincinnati.
For the 16th seeded Robredo the victory was his first over Djokovic since their first meeting in 2005, the Serb sweeping their next six meetings.
The loss brought a temporary halt to Djokovic's bid to become the first player to win all nine ATP World Tour Masters events during his career.
It was also another setback in the Serb's buildup to U.S. Open later this month after falling to Frenchman Jo-Wilfried Tsonga in the third round of the Rogers Cup last week in Toronto.
"Many, many, many things are not clicking these two weeks on hard courts," said Djokovic. "It's unfortunate but it's more than obvious I'm not playing even close to what I'm supposed to play.
"I have to keep on working and trying to get better for U.S. Open.
"I just don't feel comfortable.
"It’s disappointing that I'm finishing Cincinnati again with a tough loss but it's sport. I didn't play well in Toronto; didn't play well here.
"Hopefully it's going to be different in New York."
While Djokovic has hoisted the Canada trophy three times he has not felt the same comfort level on the Ohio hard courts, reaching the finals four times in 10 visits to Cincinnati and losing all four.
Certainly the Serb appeared out of his normal rhythm, particularly in the second set when he failed to gain even a single break chance.
Robredo managed three break opportunities and only needed to capitalise on one to secure the upset.
"I thought his forehand was really good," said Djokovic. " Served very efficiently, especially second serve. He was playing great, no question about it."
Third seeded Swiss Stan Wawrinka rallied past 14th seed Marin Cilic 3-6 6-0 6-1 to book his place in the last eight.
The Australian Open champion got off to a sluggish start losing the opening set to the big-hitting Croatian but then could do little wrong, blazing through the next two sets dropping just a single game along the way.
Unable to register even a single break chance in the first, Wawrinka broke Cilic five times over the next two sets to seal the win.
Eighth seed Andy Murray, twice a Cincinnati champion, also need three sets and two and a half hours to tame top ranked American John Isner 6-7(3) 6-4 7-6(2).
The 11th seeded Isner, a Cincinnati finalist a year ago, blasted 21 aces past his Scottish opponent but could not manage a break the entire match.
"It's a very important match for me to win," said Murray. "I had lost a few close matches, matches like that over the last few months. So, yeah, it was important for me to come through.
"It was a really, you know, good atmosphere to get ready for the rest of the tournament, but also the U.S. Open, as well."
(Reporting by Steve Keating in Toronto. Editing by Gene Cherry)