Andy Murray blew a 4-0 lead in the deciding set and lost to Albert Ramos-Vinolas 2-6, 6-2, 7-5 in the third round of the Monte Carlo Masters on Thursday.
Former French Open and Monte Carlo champion Stan Wawrinka followed Murray out after losing to Pablo Cuevas of Uruguay 6-4, 6-4.
Meanwhile, defending champion Rafael Nadal beat Alexander Zverev, spoiling the German's 20th birthday, 6-1, 6-1.
Later Thursday, two-time champion Novak Djokovic played No. 13 Pablo Carreno Busta.
Murray, returning from a right elbow injury which sidelined him during the Miami Open and Davis Cup quarterfinals, struggled on his serve in a scrappy match lasting more than 2 1/2 hours. The match featured 13 service breaks, including seven against Murray, who struggled with Ramos-Vinolas' heavy forehands in his first meeting with the Spaniard.
"I'm disappointed to lose from the position that I was in," said Murray, last year's French Open runner-up to Djokovic. "I haven't lost many matches like that in my career.
"He started playing better toward the end of the set. I should have been able to do enough to sort of weather that storm a little bit and finish the match off."
Wawrinka never found his touch or range and conceded match point when his backhand pass — normally one of the best shots in men's tennis — clipped the net and went out. Cuevas hit a sweet forehand winner down the line on the next point and raised his arms in the air after beating Wawrinka in their first-ever meeting.
Three-time Grand Slam champion Wawrinka said he felt a bit leg-weary, which left him vulnerable against a clay-court specialist.
"If you hesitate a little, he will get you," Wawrinka said. "When you're not at your top level, he knows what to do."
Zverev pushed Nadal to five sets in the third round of the Australian Open, but the only fire Zverev showed here was when he smashed his racket clean in two during the second set. It drew jeers from the center court crowd basking in the Mediterranean sun.
He conceded the match tamely, double-faulting on Nadal's third match point.
Nadal, who is chasing a 10th title here, next faces Germany's Jan-Lennard Struff or Argentine Diego Schwartzman, neither of whom is seeded.
Ramos-Vinolas faces fifth-seeded Marin Cilic in the quarterfinals. The Croatian reached the last eight after beating No. 9 Tomas Berdych 6-2, 7-6 (0).