Eighth seed Janko Tipsarevic led the way on a day of comebacks at the US Open.
Remarkably, nine players have already fought back from two sets down to win in the first round of the men's singles at Flushing Meadows, equalling the record for the whole tournament set in 1989.
Tipsarevic, who reached his first grand slam quarter-final here last year, looked like he was on his way out when he trailed French wild card Guillaume Rufin by two sets, but the Serb fought his way back to win 4-6 3-6 6-2 6-3 6-2.
Luxembourg's Gilles Muller and Estonian Ernests Gulbis were the other marathon men on Wednesday.
Muller knocked out 28th seed Mikhail Youzhny 2-6 3-6 7-5 7-6 (8/6) 7-6 (8/6), while Gulbis ended the hopes of 21st seed Tommy Haas, winning 3-6 4-6 6-4 7-5 6-3.
There were much more comfortable victories for fourth seed David Ferrer, a 6-4 6-2 7-6 (7/3) winner over big-serving Kevin Anderson, and 2009 champion Juan Martin Del Potro, who defeated lucky loser Florent Serra 6-4 7-6 (7/4) 6-4.
Del Potro, who has been struggling with a left wrist problem, had been due to face fellow Argentinian David Nalbandian but he withdrew citing a rib injury.
Ferrer, meanwhile, has been elevated into the top four because of the absence through injury of his fellow Spaniard Rafael Nadal and is seeded to meet Novak Djokovic in the semi-finals.
Although he is more renowned for his exploits on clay, Ferrer has had just as good results on hard courts and reached the last four in New York in 2007, losing to Djokovic.
Ferrer was very content with his performance, saying: "I feel good. It was not an easy match. He's a really good player, he has a very strong first and second serve."
The matches on Arthur Ashe Stadium were very one-sided over the first two days but the crowd certainly got their money's worth from the contest between home favourite John Isner and Belgium's Xavier Malisse.
Isner eventually came through 6-3 7-6 (7/5) 5-7 7-6 (11/9) while Malisse treated umpire Carlos Ramos to an ongoing tirade relating to a number of line calls, including a foul-mouthed rant at the end of the second set that earned him a formal warning.
Ninth seed Isner, who came into the tournament as one of the form players after winning the title in Winston Salem last week, said: "I knew the match today was going to be tough.
"A lot of people are projecting me to go far here, but I wasn't looking past this match. As you guys could see, I had my hands full. He doesn't mind playing me. He's played me well in the past and he did it again today.
"It got to a certain point there where it was anyone's match. I just got pretty fortunate at the end."
The success of America's Brian Baker has been one of the stories of the season and he was a 6-3 6-4 6-2 winner over Jan Hajek, seven years after his last US Open victory.
The 27-year-old was one of the world's top juniors and was beginning to make progress when injuries struck, ruling him out of the game for six years.
Most people thought Baker had retired but he gave the game one last go last summer and was so successful that he is now ranked 70th and reached the fourth round of Wimbledon as a qualifier.
Baker, who next faces Tipsarevic, said: "I remember several years watching this on TV wishing I was here, so just to be here is an awesome feeling. And then, at the same time, the competitive side kicks over and I want to do really well."
France's Richard Gasquet, the 13th seed, had to come from a set down to beat Albert Montanes 4-6 6-2 6-3 6-3, while Spain's Tommy Robredo, playing his first grand slam tournament of the year after injury, knocked out 26th seed Andreas Seppi 6-1 7-5 6-3.