Home hope Kei Nishikori was forced to withdraw from his last-16 match against Joao Sousa at the Japan Open through injury.
The top seed led 4-3 in the first set when he made the call to pull out, handing his opponent a place in the quarter-finals.
"It was hugely disappointing to have to retire from my match," said the world number five and two-time tournament winner.
"It is possible that the injury was due to an accumulation of fatigue and stress, but I came into this tournament with a lot of rest and feeling very ready.
"I will get examined and hope to recover in time for my next tournament."
Wednesday's play also saw third seed Tomas Berdych fall to a 7-6 (9-7) 6-1 defeat in his first-round showdown with Gilles Muller.
Those two high-profile exits have blown the tournament wide open, with Marin Cilic among those to take advantage as he came from behind to beat Fernando Verdasco 4-6 7-5 7-5.
Also in Tokyo, David Goffin overcame Jiri Vesely 6-3 7-5, and Juan Monaco proved too strong for James Duckworth, 7-6 (7-3) 6-3.