Wimbledon champion Novak Djokovic was shocked for the second week in a row on Thursday as Spain's Tommy Robredo knocked the top seed out of the Cincinnati Masters.
Robredo, seeded 16th in the US Open tune-up, ousted Djokovic 7-6 (8/6), 7-5, the defeat coming a week after the world number one Serb was beaten in the third round at Toronto.
He now goes into the US Open, the final Grand Slam of the year which starts on August 25, well short of matches and confidence.
Djokovic was married last month and is soon to become a father, new factors which could be weighing on his tennis.
"I just lost the match. It was bad. Many, many things are not clicking these two weeks on hard courts. It's unfortunate, but it's more than obvious I'm not playing even close to what I'm supposed to play," said Djokovic.
"I have to keep on working and trying to get better for the US Open. I just don't feel comfortable. That's it."
Robredo won only his second match in eight encounters with a world number one player. He beat then-top ranked Lleyton Hewitt at Roland Garros 11 years ago.
"It's amazing to be here playing and to beat the number one, I'm more than happy," said the 32-year-old Robredo, who had lost six straight matches to Djokovic.
Djokovic was also denied the chance to stay in the chase for the one Masters 1000 title he does not own as he went down to Robredo in one and three-quarter hours.
Andy Murray battled more than two hours against the huge serve of John Isner, finally dispatching the American 6-7 (3/7), 6-4, 7-6 (7/2) to reach the quarter-finals.
Two-time champion Murray saved a pair of match points in the 12th game of the third set as Isner hit the net with errors.
- Murray, Serena in quarters -
The American was then caught by a passing shot before Murray levelled at 6-6 with an ace.
The Scot bore down in the decisive tiebreaker, ending the match with his 14th ace.
Murray, in search of his first title since Wimbledon in 2013, has struggled to regain top form since his return from back surgery in January.
"It's a very important match for me to win,"said Murray. "I had lost a few close matches over the last few months. It was important for me to come through.
"It was completely packed crowd from the first point right until the end. It was really a good atmosphere to get ready for the rest of the tournament, but also the US Open, as well."
Murray next faces either second-seeded Roger Federer or Gael Monfils as he tries to add a third Cincinnati title to those he won in 2008 and 2011.
Isner, runner-up to Rafael Nadal in Cincinnati last year, was denied another shot at the title, with 21 aces not enough to see him through.
Australian Open champion Stan Wawrinka, the third seed, rallied to beat Croatian Marin Cilic 3-6, 6-0, 6-1 while Italian 15th seed Fabio Fognini recovered to eliminate Lu Yen-Hsun of Taiwan 3-6, 6-3, 6-3.
Frenchman Julien Benneteau advanced into the last eight with a 7-5, 6-1 win over Poland's Jerzy Janowicz.
Fifth seed Milos Raonic made amends with his 30th ace on match point -- having earlier double-faulted three times while serving for victory.
The Canadian defeated American Steve Johnson 6-7 (7/9), 6-3, 7-6 (7/4).
In women's action in the combined ATP and WTA event, defending champion Serena Williams continued her march through the draw, beating Italian 13th seed Flavia Pennetta 6-2, 6-2.
Also through was world number two and second seed Simona Halep, a 6-4, 7-5 winner against Czech Lucie Safarova.
"Today was much better than my first match here," said Halep, winner in Bucharest last month and runner-up to Maria Sharapova at Roland Garros. "I was happy to win in two sets, since she was up 5-4.
Ukrainian teenager Elina Svitolina, who took out double Wimbledon winner Petra Kvitova in the second round, claimed her second seeded victim with a defeat of Spain's number 15 Carla Suarez Navarro 4-6, 6-4, 6-4.
Sharapova, seeded fifth, defeated fellow Russian Anastasia Pavlyuchenkova 6-4, 7-6 (7/2). Eighth seed Jelena Jankovic defeated Sloane Stephens 7-6 (7/4), 6-4.