The three hour, 31 minute quarter-final was played in suffocating humidity so extreme that officials called a halt to junior matches on the outside courts for more than two hours.
Play continued on Arthur Ashe but with temperatures nudging 100 degrees Fahrenheit (37.7°C) the stadium was turned into a sauna, leaving the 6'10" (2.08m) American Isner and 6'6" (1.98m) Argentine Del Potro, suffering.
"I weigh 238 pounds, so I have always said it's pretty difficult to play in hot conditions," said Isner, who had 11 shirt changes during match. "I weigh a lot and I sweat a lot.
"It takes its toll on bigger guys, in my opinion.
"I don't know what I weighed before the match. I did not weigh myself, but I can tell you I lost a lot of weight out there."
Anyone looking for serve and volley came to the wrong place as the pair traded bombs from the baseline with Isner, bidding to become the first American since Andy Roddick in 2006 to reach U.S. Open semi-finals, belting 26 aces and Del Potro 14.
Break chances were few and far between, Isner managed just three and was unable to convert any, while Del Potro had 11, cashing in on three, including one to close out the match.
It was enough to see Del Potro, the 2009 U.S. Open champion, through to the last four at Flushing Meadows for a third time where he will face either top seed Rafa Nadal or Austrian ninth seed Dominic Thiem, who were playing later on Tuesday.
"I think I played very solid this game," said Del Potro. "In particular I made good returns every service game.
"I saw John a little bit tired also. That's give me a little bit more energy to keep trying.
"I don't know if I'm playing my best tennis ever but I'm feeling good. I reach another semi-finals in this grand slam, which means something big to me."
The Argentine had the sole break chance in the opening set but the third seed could not convert, while Isner had a mini-break at 3-3 in the tiebreak and turned that into a 1-0 lead.
It was the first set surrendered by Del Potro at the tournament this year and a positive omen for 11th seed Isner, who was 24-2 at Flushing Meadows when winning the first set.
But Del Potro would not drop another set as the Argentine appeared better equipped to deal with the conditions even though he joked he did not want to come back on court following a 10-minute break between the third and fourth sets.
"I had a shower, lay on the table and I didn't want to come back again," laughed Del Potro.
"It was too hot for tennis."
(Editing by Ken Ferris)
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