Two five-set contests in three days proved too much for John Isner on Friday and his exit left the United States without a single man standing in the last 16 of the Australian Open for the first time since 1973.
The American number three, who went the distance to beat Argentine David Nalbandian in the second round on Wednesday, bowed out at the third round stage 6-3 6-7 6-4 6-7 6-1 at the hands of Spain's Feliciano Lopez on Hisense Arena.
"It's very disappointing," Isner told reporters. "That's not a good effort from the Americans this tournament. And I knew going in today I was the last one left and I wanted to keep on going, but just didn't happen.
"But it's very ugly, to be honest, to have no one in the round of 16. We've got to try to rectify that next time the big tournaments roll around."
Eleven American men played in the first round earlier this week with six, including seeds Isner, Mardy Fish and Andy Roddick, making it through to the second round.
Fish, the eighth seed, was upset 7-6 6-3 7-6 by Colmbian Alejandro Falla on Wednesday while former U.S. Open champion Roddick, seeded 15th, retired with a hamstring injury while losing his second round tie to Lleyton Hewitt on Thursday.
Donald Young, Sam Querrey and Ryan Sweeting also lost, leaving just 16th seed Isner representing the most successful nation in the history of the game.
There were no American men in the fourth round in 1972 and 1973 because none entered the tournament. Otherwise there has always been at least one player from the U.S. in the men's last 16 since tennis went professional in 1968.
Isner's exit marks a new low for the U.S., who last year were left without a representative in the men's or women's quarter-finals for the first time since 1987, when not all top players made the trip Down Under.
Vania King and Serena Williams, who missed her title defence at Melbourne Park last year because of injury, will have a chance to keep the Stars and Stripes flying in the women's draw in the third round on Saturday.