Former champion Juan Martin del Potro became the lowest ranked player in 25 years to reach the US Open quarter-finals when Dominic Thiem quit their last-16 tie through injury on Monday.
The 142nd-ranked Argentine was leading 6-3, 3-2 when the eighth-seeded Austrian retired with a right knee injury having received a medical timeout just moments earlier.
Del Potro, the 2009 champion who was pushed to the brink of retirement earlier this year after undergoing three surgeries on his left wrist, will face either Stan Wawrinka or Illya Marchenko for a semi-final place.
Jimmy Connors was ranked 174 when he went on to the US Open semi-finals in 1991.
"You never want to win a match like this. I wish Dominic a quick recovery as he has a great future," said 27-year-old del Potro.
The giant Argentine had required treatment himself on a right shoulder injury after dropping serve to go 2-1 down in the first set.
But he recovered to break back for 3-3 before edging ahead at 5-3 and taking the opener on an ace.
Del Potro was a break to the good again at 2-1 in the second set before Thiem began to flag.
The 23-year-old Austrian had needed five sets to beat Australia's John Millman in the first round and four to get past Pablo Carreno Busta of Spain in the last 32.
He was also playing in a season-leading 70th match of the season and 21st tournament, a gruelling schedule which finally caught up with him on Arthur Ashe Stadium on Monday.
"I couldn't bend my knee too much in the last three days so I was handicapped," said Thiem who said he was also suffering blisters on his feet.
"You can't take too many risks with the knee."
Should del Potro make the semi-finals, he would be the lowest-ranked man to do so at a Grand Slam since 237-ranked Vladimir Voltchkov at Wimbledon in 2000.
No man ranked as low as del Potro has ever made the final of a major.
"It's amazing to play in New York. There's a great connection between the US fans and Argrentina fans," said del Potro who was handed a wildcard for the US Open after winning the silver medal at the Olympics.
"I don't know if I am playing better than I was in 2009 but I will try to keep winning."
Murray in action
Andy Murray, the 2012 champion, who has reached the last 16 or better for the 23rd straight Slam, will open the night session against resurgent Bulgarian Grigor Dimitrov.
Murray leads the head-to-head with Dimitrov 6-3 although the 25-year-old Bulgarian won their last match in Miami in March.
Japan's sixth seed Kei Nishikori has made the fourth round of all the majors in the same year for the first time.
The 2014 runner-up takes on in-form Ivo Karlovic who, at 37, is the oldest player in the fourth round since 39-year-old Connors made the semi-finals in 1991.
Having saved a match point in an epic triumph over Dan Evans in the last round, third-seeded Wawrinka, a semi-finalist in 2013 and 2015, faces 28-year-old Ukraine journeyman Marchenko.
World number 63 Marchenko arrived in New York on a seven-match losing streak, a run of failure stretching back to Istanbul in April.
The first two quarter-finals take place on Tuesday when defending champion Novak Djokovic faces France's Jo-Wilfried Tsonga and Lucas Pouille, the conqueror of Rafael Nadal, tackles French compatriot Gael Monfils.
It's the first time since 1947 that three French men have reached the quarter-finals of one Grand Slam.