Argentina's Juan Martin del Potro eased past Filippo Volandri of Italy in his first match at Flushing Meadows since winning the title in 2009.
Del Potro, 22, stunned Roger Federer in the final two years ago but missed most of 2010 with a wrist injury.
Now seeded 18th as he works his way back up the rankings, Del Potro eased past Volandri 6-3 6-1 6-1 in round one.
In the night session, 2003 champion Andy Roddick had to work hard for a 6-2 6-4 4-6 7-5 win over Michael Russell.
Roddick, 29, let his fellow American back into the match from two sets up but edged through in just under three hours to set up a meeting with another compatriot, Jack Sock.
Earlier on day three, sixth seed Robin Soderling pulled out of the tournament because of illness.
"He had an upset stomach," said Soderling's agent. "He experienced head pain and the doctor recommended to him not to play.
"They don't know what kind of virus it is but the doctor thinks it can be something related to the throat problems he had a couple of weeks ago, which made him have to withdraw from the Masters tournament."
The 27-year-old Swede was replaced by Brazil's Rogerio Dutra Da Silva, who then further profited from the call when Irish opponent Louk Sorensen was also forced to retire.
Del Potro was unable to defend his title last year as he recovered from the wrist injury that sidelined him from January to September of 2010.
This season the Argentine has been steadily rebuilding his ranking, winning titles at Delray Beach and Estoril and reaching the semi-finals in three other tournaments.
"I keep improving very slowly," said Del Potro. "That's important. I think I'm serving much better than two years ago or at the beginning of this year.
"I know that other players are playing much better than me at this moment, especially the top-10 players. But to be here playing this tournament, for me it's a great signal for my future. I know I'm getting closer to my best level, and that's important."
Big-serving American John Isner defeated Cypriot Marcos Baghdatis 7-6 (7-2) 7-6 (13-11) 2-6 6-4 in an entertaining contest - their third in the last four tournaments, all of which have gone Isner's way.
with a straightforward 7-6 (7-5) 6-2 6-3 win over Somdev Devvarman, and 12th seed Gilles Simon defeated Ricardo Mello 3-6 6-3 6-4 3-6 6-4.
There was a surprise, at least in terms of rankings, when Spain's 10th seed Nicolas Almagro went down 6-2 6-4 6-3 to French wildcard Julien Benneteau,the world number 81.
And there was a major shock in the men's doubles as top-ranked Americans Bob and Mike Bryan lost 6-4 2-6 6-2 to unseeded duo Ivo Karlovic and Frank Moser, the twins' first opening-round defeat at a Grand Slam tournament since 2001.
Britain's Colin Fleming and Ross Hutchins defeated Martin Damm and Radek Stepanek 6-3 6-3, and Jamie Delgado and Jonathan Marray beat Matthias Bachinger and Philipp Kohlschreiber 6-3 6-7 (5-7) 6-4.
However, Jamie Murray and Mexico's Santiago Gonzalez lost 6-3 6-0 to ninth seeds Jurgen Melzer and Philipp Petzschner, and Murray also went out of the mixed doubles with Nadia Petrova 6-2 6-7 (7-9) 10-6 against seventh seeds Elena Vesnina and Leander Paes.