A shoulder injury ended American sixth seed Ben Shelton’s hopes of victory at his home Grand Slam.
The 22-year-old led veteran Frenchman Adrian Mannarino by two sets to one on Louis Armstrong Stadium when the issue first appeared to surface early in the fourth set.
After receiving treatment during a medical time-out, Shelton played on but regularly grimaced and grasped his left shoulder after hitting forehands from then on.
His powerful serve did not seem to be affected too much, but he was broken midway through the fourth set and when Mannarino took it 6-4 to level the match, a tearful Shelton chose to retire before the start of the decider.
It is the first time in 178 career matches that Shelton has had to retire.
“When he started to have pain, he was leading and would have probably won the match,” said 37-year-old Mannarino, who is through to the last 16 of the US Open for the first time in 15 attempts.
“It’s unfortunate for him and very lucky for me. I don’t really know what to say – of course I’m happy to get through and I wish him the best.”
Mannarino will play Czech 20th seed Jiri Lehecka next, following his straight-set win over Belgium’s Raphael Collignon.
Elsewhere, Shelton’s compatriot Frances Tiafoe was beaten 6-4 6-3 7-6 (9-7) by German qualifier Jan-Lennard Struff.
Struff – who knocked out 11th seed Holger Rune in the second round – was broken when serving for the match in the third set, but held his nerve in the tie-break to complete a straight-set win.
He will face either 24-time Grand Slam champion Novak Djokovic in round four.
There was better news for home fans with American fourth seed Taylor Fritz beating Swiss Jerome Kym 7-6 (7-3) 6-7 (9-11) 6-4 6-4.
Tommy Paul, the only other American man left in the draw, faces 23rd seed Alexander Bublik in the third round on Saturday.