US hopes at the French Open were extinguished on Thursday as marathon man John Isner was once again involved in an epic duel, the fourth longest in grand slam history, which this time he lost.

The giant Isner found himself as the last American standing out of eight starters after qualifier Jesse Levine had earlier gone down 6-4 7-5 6-2 to Milos Raonic of Canada.

But after what turned out to be, at five hours 41 minutes, the second longest match in French Open history and the fourth longest in grand slam history, Isner lost 6-7 (2-7) 6-4 6-4 3-6 18-16 to French wildcard Paul-Henri Mathieu.

Mathieu finally entered the third round by converting his seventh match point, Isner hitting a forehand wide.

The American hit 41 aces, but had 98 unforced errors.

Ironically, it was against another Frenchman, Nicolas Mahut, that Isner played the longest match in history at Wimbledon in 2010 when he took 11 hours and five minutes, spread over three days, to win 6-4 3-6 6-7 7-6 70-68.

At no point, Isner insisted did his mind travel back nearly two years ago to the match with Mahut which has gone down in the annals of sporting history as one of the greatest athletic contests of all time.

“No, I mean, it’s more disappointing on how I lost it,” he said.

“I just couldn’t free myself up the whole match … but he’s a good player, and he was better than me today. He deserved to win.”

The loss means the American drought in grand slam titles moves on to 34 dating back to when Andy Roddick won the 2003 US Open.

The last American winner in the French Open was Andre Agassi in 1999 and he was also the last American to reach the quarter-finals four years later.

The win for 30-year-old Mathieu came after he spent 15 months out of the game with a serious injury to his left knee that required extensive surgery.

He only returned to action early this year and his ranking had fallen so low he needed a wildcard to get into the main draw at Roland Garros.

Mathieu said he had sought out Mahut for some tips on how to counter Isner’s power before the match.

“I asked Nicolas for some advice. I asked him where did he serve on break points, and he said, ‘he serves everywhere’.

“But I said, there’s certainly a serve he does more often. He said, ‘No, he serves everywhere. He’s unpredictable’.

“My tactics was just to return his serve whenever I could and, at the end of the match, to make him run as much as I could right and left.”