Wimbledon finalist Tomas Berdych crashed out of the US Open in the first round after losing in straight sets to France's Michael Llodra.
World number 35 Llodra just missed out on being seeded for the main draw, but proved why he was a player many of the seeds wanted to avoid with a 7-6 6-4 6-4 victory.
The 30-year-old left-hander had lost in the first round in 22 of his previous 36 Grand Slam singles events, but drove seventh seed Berdych to distraction with his serve-and-volley tactics.
"I don't know whether I played well or not," complained Berdych, who knocked defending champion Roger Federer out in the quarter-finals at Wimbledon but lost in straight sets to Rafael Nadal in the final.
"I had no chance to play on my terms. I don't see what I could have done better or differently."
Llodra will play Victor Hanescu in the second round after the unseeded Romanian beat Carlos Berlocq of Argentina 6-2 6-4 6-3.
Fifteenth seed Ivan Ljubicic of Croatia was beaten in four sets by 18-year-old American qualifier Ryan Harrison.
"The weather was my biggest enemy today," admitted 31-year-old Ljubicic.
"Throughout my career I struggled with the heat. Today was no different.
"I sweat a lot and I just feel really bad. I mean, I can't move. It gets to me really quickly actually. Already in the first set I was struggling with it. It's really a physical problem."
Asked if he would be in favour of the 'heat rule' - which allows players a 10-minute break after the second set - being applied to the men's game as well as the women's, Ljubicic joked: "I would be in favour of an indoor tour altogether, if you ask me.
"We saw some players struggling big time. There are comments saying it's the same thing for everybody, but really it's not. Somebody is struggling more than others, and I think it's just not fun.
"I think people out there are coming to see good tennis, and on days like this it's all about everything except tennis. It's just trying to hang in there and hit some balls more on the court than the other guy or other girl, whoever plays.
"A break doesn't really help. In Australia they have a pretty good rule. When it's too hot, you just don't play. Hard courts definitely make it worse. The concrete, it's just brutal. You get heat not only from the sky, but also from the bottom."
A delighted Harrison said: "It's definitely the biggest one of my career so far. To win on this stage here and to take out a top 20 player in the world is the biggest win of my career.
"I've always believed in myself. I have always had confidence in myself, so obviously I'm extremely excited and really pleased with what happened.
"But by the same token, I'm really going to look forward to trying to get back into my routines on the day off and looking forward to trying to get ready for the second round."
Another American winner was 20th seed Sam Querrey, who needed four sets to beat compatriot Bradley Klahn.