Monte Carlo - Andy Murray surrendered a 4-0 lead in the decisive third set on his way to defeat at the Monte Carlo Masters on Thursday as the world number one's 2017 season hit another setback.
Murray suffered a shock third-round loss to Spain's 15th seed Albert Ramos-Vinolas 2-6, 6-2, 7-5 in more than two and a half hours.
Former French Open champion Stan Wawrinka was also routed, with the Swiss third seed losing to Pablo Cuevas of Uruguay 6-4, 6-4.
Rafael Nadal gatecrashed Alexander Zverev's 20th birthday party with a brutal 6-1, 6-1 demolition while Novak Djokovic battled past Pablo Carreno Busta 6-2, 4-6, 6-4.
Ramos-Vinolas toppled Scottish top seed Murray on his second match point to progress to the quarter-finals on the Monaco clay for the first time at the French Open warm-up event.
"I'm disappointed to lose from the position that I was in," said 29-year-old Murray, who was making his first ATP appearance this week since a second-round loss to Vasek Pospisil at Indian Wells on March 12.
"If you look at the scoreline, it was 7-5 in the third. One week ago I would have been okay with that. But sitting here, being 4-Love up in the third, I haven't lost many matches like that in my career.
"I'm disappointed. I feel like I had enough chances to win. I was close, I think. Maybe tomorrow or a day after I'll be able to look back a little bit and think where I'm at now from where I was a week ago.
"My elbow felt pretty good. I served much better today than I did yesterday. That's only going to get better. So hopefully I keep going in the right direction."
Defending champion Nadal, chasing a 10th title at the tournament, will face Argentina's Diego Schwartzman, who beat German qualifier Jan-Lennard Struff 6-3, 6-0.
"I played well. I played much better than yesterday. I played more aggressive, I played with a very high intensity from the beginning," Nadal said.
"I'm playing much better with my forehand. I maintained that kind of level for all the match, I think that was the key."
Second seed Djokovic got past Carreno Busta, leaving the 13th seeded Spaniard standing 0-16 against top 10 opponents.
The French Open champion had needed three sets to get past Gilles Simon in his opening match at the clay court showpiece and goes on to face Belgium's David Goffin for a semi-final spot.
Victory for Vinolas-Ramos marked the first time the 29-year-old from Barcelona, who reached last year's French Open quarter-finals, had got the better of a world number one.
His reward is a Friday quarter-final against Croatian fifth seed Marin Cilic, who motored past number ninth seed Tomas Berdych 6-2, 7-6 (7/0).
Results at the Monte Carlo Masters on Thursday (x denotes seeding):
Albert Ramos Vinolas (ESP x15) bt Andy Murray (GBR x1) 2-6, 6-2, 7-5
Marin Cilic (CRO x5) bt Tomas Berdych (CZE x9) 6-2, 7-6 (7/0)
Pablo Cuevas (URU x16) bt Stan Wawrinka (SUI x3) 6-4, 6-4
Lucas Pouille (FRA x11) bt Adrian Mannarino (FRA) 3-0 - retired
Diego Schwartzman (ARG) bt Jan-Lennard Struff (GER) 6-3, 6-0
Rafael Nadal (ESP x4) bt Alexander Zverev (GER x14) 6-1, 6-1
David Goffin (BEL x10) bt Dominic Thiem (AUT x6) 7-6 (7/4), 4-6, 6-3
Novak Djokovic (SRB x2) bt Pablo Carreo-Busta (ESP x13) 6-2, 4-6, 6-4