New York - Juan Martin del Potro reached the US Open semi-finals for the third time on Tuesday, defeating John Isner 6-7 (5/7), 6-3, 7-6 (7/4), 6-2 and ending American hopes of a first men's champion at the event since 2003.
Argentine third seed Del Potro, the champion in 2009, goes on to face either world number one and defending champion Rafael Nadal or Austria's Dominic Thiem for a place in the final.
Del Potro dropped his first set of the tournament against 11th seed Isner, who was playing in his maiden quarter-final at his home Slam.
Despite that, the 29-year-old was never broken in the 3 hour 31 minute match where Isner unleashed 26 aces but was undone by 52 unforced errors compared to Del Potro's 14.
"To reach the semi-final again here in New York in my favourite tournament is very special to me," said Del Potro after his eighth win over Isner in 12 meetings.
"To play John in these kind of matches, it's like an epic.
"We fought the whole match and I survived with my serve which was key."
Del Potro admitted the 33-degree temperatures proved a real challenge with the 10-minute heat rule allowing the players a welcome respite after the third set.
"I had a shower, lay on the table and I didn't want to come back again. It was too hot to play tennis," he joked.
Del Potro carved out the only break point of the first set in the 11th game but was unable to convert before the 33-year-old Isner claimed the tie-break with his ninth ace.
That was the first set dropped by Del Potro at the tournament.
Another break point came and went for the Argentine in the second set before he deservedly broke through for 3-1, backed up by a love service hold.
He comfortably levelled the contest, giving up just three points on his own serve in the set.
Del Potro saved the only two break points he faced in the entire match in the fourth game of the third set which he wrapped up in another tiebreak.
Isner was a spent force in the fourth and Del Potro drove in the dagger with a break in the second game consolidated by another in the eighth.
Now he looks ahead to a semi-final where he will either take a 5-11 losing record against Nadal or a perfect 4-0 over Thiem.
Isner, meanwhile, will return to Dallas as quickly as he can where his wife is due to give birth to their first child in two weeks' time.
Later Tuesday, Nadal continued his pursuit of a fourth title in New York against Thiem, the man he beat to clinch an 11th French Open in June.
Nadal holds a 7-3 career lead over the 25-year-old but Tuesday's clash under the Arthur Ashe lights will be their first away from a clay court.
Nadal, 32, is the only man to have reached the quarter-finals of all four Slams this year.
Victory will put him into a 29th semi-final at the majors.
Thiem, the ninth seed, is bidding to become the first Austrian to reach the semi-finals of the US Open.
Wednesday's quarter-finals will see two-time champion Novak Djokovic face Australia's John Millman, the world number 55 who shocked Roger Federer in the last 16.
Marin Cilic will face Kei Nishikori in a repeat of the 2014 final won by the giant Croat.
US Open results on Tuesday, the ninth day of the 2018 tournament at Flushing Meadows (x denotes seeded player):
Juan Martin del Potro (ARG x3) bt John Isner (USA x11) 6-7 (5/7), 6-3, 7-6 (7/4), 6-2
Serena Williams (USA x17) bt Karolina Pliskova (CZE x8) 6-4, 6-3
Anastasija Sevastova (LAT x19) bt Sloane Stephens (USA x3) 6-2, 6-3