World number eight Rafael Nadal is out of the US Open after losing a five-set, third-round thriller to Italian Fabio Fognini at Flushing Meadows.
Nadal, the winner of 14 Grand Slam titles, won the first two sets, but lost the next three as he was beaten 3-6 4-6 6-4 6-3 6-4.
It is another poor result for the 29-year-old, who lost to Dustin Brown in the second round at Wimbledon.
World number 32 Fognini, 28, faces Spain’s Feliciano Lopez in round four.
Meanwhile, Serena Williams was two games from defeat before recovering to beat Bethanie Mattek-Sands and keep her Grand Slam hopes alive at the US Open.
The world number one came back to win 3-6 7-5 6-0 in round three at Flushing Meadows.
Williams, 33, is aiming to become the first player to win the calendar Grand Slam since 1988.
Men’s top seed Novak Djokovic progressed, with former champion Rafael Nadal to play later on Thursday.
“I’m not trying to live on the edge,” said Williams after another tense victory edged her closer to making history.
Williams’ fightback against fellow American Mattek-Sands, ranked 100 places lower, means she remains on course to meet older sister Venus in the quarter-finals in New York.
Two-time champion Venus Williams, the oldest player in the draw at 35, upset 18-year-old 12th seed Belinda Bencic in a 6-3 6-4 win.
For the fifth time in her last six matches she fell a break behind, and for the 13th time this year she dropped the first set, but once again Williams found a way to win.
With Mattek-Sands, 30, showing the attacking skills that won her the Australian and French Open doubles titles this year, Williams could not find her feet for the first hour.
The 21-time Grand Slam champion was visibly tense, repeatedly screaming “Come on!” and looking pleadingly at her support team as 11 of 12 break points slipped by.
Her edginess was clear for all to see when two double faults saw her broken when serving for the second set, but three rasping returns finally got her over the line.
Williams, 33, had won all nine of her deciding sets at Grand Slams in 2015 and an early break set her on course to making it 10 out of 10.
Mattek-Sands was swept aside in a final set that lasted 25 minutes, and Williams said: “Players come out really strong – I don’t think I came out too slow.
“I was finally able to get some rhythm going in the second. I said, ‘You know what Serena, just keep going, keep trying.'”
Williams will next face another American, 19-year-old 19th seed Madison Keys, who beat Agnieszka Radwanska 6-3 6-2.
Swiss teenager Bencic was only six months old when Venus Williams, unseeded and ranked 66th, made a stunning run to the 1997 final before losing to Martina Hingis.
Eighteen years on, the Swiss great was watching from the stands on Arthur Ashe Stadium as part of her teenage compatriot’s team.
Bencic is the only player to have beaten Serena Williams on a hard court this year, but if both sisters remain on course it could now be Venus who provides the major obstacle to her sister’s hopes of a calendar Grand Slam.
World number one Djokovic served out against third-round opponent Andreas Seppi at the second attempt to win in straight sets.
The Serb, 28, lost his serve at 5-4 in the third set, only to instantly break back against the 25th-seeded Italian.
Seppi earned two more break points in what turned out to be the final game, only for Djokovic to rediscover his first serve at the perfect time to close out a 6-3 7-5 7-5 victory.
Djokovic revealed afterwards that he had been feeling dizzy on court, saying: “At the beginning, first set, I was struggling. I managed to break through and felt better after that.”
Defending champion Marin Cilic saved two set points against Kazakhstan’s Mikhail Kukushkin before winning 6-7 (5-7) 7-6 (7-1) 6-3 6-7 (3-7) 6-1 in four hours and 11 minutes.
Top-10 ranked players Milos Raonic and David Ferrer were both eliminated, with Ferrer’s conqueror Jeremy Chardy remaining on course to face fellow Frenchman Jo-Wilfried Tsonga – who eased past Ukraine’s Sergiy Stakhovsky in straight sets – in the quarter-finals.
