An ankle injury put paid to John Isner's chances of reaching the second round of the Australian Open.
The 13th seed surprised himself by winning the ATP Tour title in Auckland last week despite the problem but had to retire trailing qualifier Martin Klizan 6-2 7-6 (8/6) in Melbourne.
That section of the draw is now wide open after 21st seed Philipp Kohlschreiber pulled out before the start of play because of a hamstring problem.
One of those two had been expected to reach the fourth round, where they were seeded to meet world number four Andy Murray.
Isner is, though, expecting to be fit to take on Murray's Great Britain side in Davis Cup the week after the Australian Open.
Tenth seed Jo-Wilfried Tsonga was a comfortable 7-5 6-3 6-3 winner over Italy's Filippo Volandri while Japanese 16th seed Kei Nishikori needed a punishing three hours and 41 minutes to defeat Australian Marinko Matosevic in five sets.
Canadian Frank Dancevic was one of the worst victims of the heat, the qualifier collapsing on the court during his match against 27th seed Benoit Paire.
Remarkably, Dancevic carried on but unsurprisingly lost in straight sets.
Eleventh seed Milos Raonic and Grigor Dimitrov, seeded 22nd, both came through in four sets.