Novak Djokovic suffered his earliest loss at a tournament for three years with a shock defeat by Czech Jiri Vesely at the Monte-Carlo Masters.
Vesely, a 22-year-old ranked 55, had never previously beaten a top-10 player but stunned the world number one and defending champion 6-4 2-6 6-4 in the second round.
Djokovic's only previous singles loss in 2016 had come when an eye infection prompted his retirement against Feliciano Lopez in Dubai.
And the Serbian, who had a bye in round one, had not lost his opening match at any tournament since the Madrid Masters in 2013.
Djokovic was out of sorts throughout but Vesely more than played his part, losing just two points on serve in the opening set and then hitting back in the decider after losing the last four games of the second set.
At that stage, Djokovic seemed to have overcome the danger but Vesely got the better of three successive breaks at the start of the third.
Djokovic saved a match point to hold for 5-4 but Vesely put nerves aside to take his second chance when the top seed put a forehand wide.
The result was all the more remarkable given Vesely won just one match in his first seven tournaments of the year, only finding form last week in Marrakech with a run to the semi-finals.
Eight-time winner Rafael Nadal had no such problems in a 6-3 6-3 victory over Britain's Aljaz Bedene and next meets rising star Dominic Thiem, who recovered from a set down to defeat Japanese qualifier Taro Daniel.
Fourth seed Stan Wawrinka, the champion in 2014, battled past Philipp Kohlschreiber 7-6 (7/2) 7-5 but sixth seed Tomas Berdych suffered a surprise 6-4 6-7 (1/7) 6-3 loss to Bosnian Damir Dzumhur.
David Goffin and Milos Raonic both survived final-set tie-breaks to defeat Fernando Verdasco and Pablo Cuevas respectively while 16th seed Benoit Paire saw off Joao Sousa.