American Jack Sock had to retire against Ruben Bemelmans after he collapsed onto the court amid the intense heat at the U.S. Open on Thursday.
Sock, seeded 28th, led the match two sets to one. He also retired last year at the U.S. Open due to a calf injury.
Andy Murray, the champion in 2012, fell behind two sets to Frenchman Adrian Mannarino before cruising in the next three.
Stan Wawrinka, like Murray a two-time grand slam champion, was tested by South Korean teen Hyeon Chung but advanced in three tiebreaks.
Murray has appeared in the semifinals, at least, in all three majors this season.
Victoria Azarenka, a two-time U.S. Open finalist, won in two sets against Yanina Wickmayer.
Many consider Azarenka to be Serena Williams' biggest threat in New York. Williams is attempting to win all four majors in one season.
Garbine Muguruza, who made the Wimbledon final and lost to Williams, was upset by qualifier Johanna Konta. Muguruza, pictured, cut ties with her coach last week.
Sam Stosur, the 2011 winner, spent less than an hour on court in defeating Evgeniya Rodina. But she criticized tournament organizers for the way they handle transportation.