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Djokovic's status as an unvaccinated player has limited his ability to compete on the tour this year. He missed the Australian Open in January after a saga surrounding his visa eventually resulted in his deportation on public health grounds, while laws around vaccination against COVID-19 in the United States prevented him from playing at Indian Wells and Miami.

WATCH: Tsitsipas kicks off Monte Carlo title defence in style

Despite his inactivity, the Serbian - whose sole appearance on tour this year came during a run to the quarter-finals in Dubai - was expected to prevail on the clay against his Spanish opponent after receiving a bye in the first round.

But there were evident signs of rust in a mistake-riddled display against the world number 46, who remarkably emerged victorious to set up a meeting with either Dan Evans or David Goffin.

The tide looked to have turned in the second set tie-break, when an exquisite whipped forehand from Djokovic sent the match to a decider.

However, Djokovic, who committed 51 unforced errors, immediately surrendered the momentum by dropping serve in the first game of the third and he was broken twice more as Davidovich Fokina powered to a 6-3 6-7 (5-7) 6-1 victory in just under three hours.

"I knew that Nole hasn't had that confidence because he didn't play a lot," Davidovich Fokina said.

"This win is so special for me. I look at him every tournament. Here in Monte Carlo, full people [capacity], against the number one, I enjoy every moment."

Earlier, Evans saw off Benjamin Bonzi while Goffin, fresh off his triumph in Marrakech, came through against Jiri Lehecka to set up their second-round meeting.

Tenth seed Taylor Fritz defeated Monegasque wild card Lucas Catarina in three sets and 16th seed Lorenzo Sonego saw off Ilya Ivashka in straight sets. Laslo Djere, a semi-finalist in Marrakech, also progressed to the second round.