Novak Djokovic said he "ran out of gas" as he lost his opening match at the Monte Carlo Masters on Tuesday in just his second tournament of the year following his refusal to get vaccinated against Covid-19.

The world number one went down 6-3, 6-7 (5/7), 6-1 to 46th-ranked Spaniard Alejandro Davidovich Fokina in the second round after dropping his serve nine times in a rusty performance.

"I was hanging on the ropes the entire match. I was really chasing the result constantly," said Djokovic, whose only other appearance in 2022 was in Dubai in February where he played just three matches.

"I didn't like the way I felt physically in the third (set). I just ran out of gas completely.

"Just couldn't really stay in the rally with him. If you can't stay in the rally, not feeling your legs on the clay, it's mission impossible."

Djokovic admitted his absence from most events had been "difficult, mentally and emotionally" but said he was "moving on" ahead of his return at a tournament he won in 2013 and 2015.

Davidovich Fokina had lost both previous meetings to Djokovic in straight sets, in Rome and at the Tokyo Olympics last season, but he raced into a 4-1 lead and took the first set.

The Spaniard surged 3-0 ahead in the second only for Djokovic to win five of the next six games and serve for the set at 5-4.

He failed to do so at the first attempt but recovered in the tie-break to force a decider.

Davidovich Fokina broke to start the third set as Djokovic double faulted, and there was no way back this time for the top seed and 20-time Grand Slam champion.

Novak Djokovic has played just four matches this season
Novak Djokovic has played just four matches this season AFP / Valery HACHE

"I always believed that I could come back and win the match, and I stayed there even though a lot of things were against me in terms of how I felt on the court," said Djokovic.

"Game-wise, physically I was just far from my best."

"Of course in those types of conditions and circumstances, then you have to really work two times more than you normally would," he added.

"I expected this match to be a really tough match, a physical battle, and that's what it was. Unfortunately I'm on the shorter end of the stick, and my week ends here."

It marks the first time Djokovic has lost his opening match at a tournament since falling to Martin Klizan at Barcelona four years ago.

He has not gone beyond the quarter-finals in Monte Carlo since 2015.

"I knew a few days ago when I spoke to you that it's going to take some time for me to really feel my best on the clay," said Djokovic.

"That's historically always been the case. I have never played very well in the opening tournaments of the clay season.

"But it's okay. Obviously it is what it is. I have to accept the defeat and keep working."

Davidovich Fokina, a quarter-finalist here on his debut a year ago, will play David Goffin or Dan Evans for a place in the last eight.

Defending champion Stefanos Tsitsipas eased into the last 16 with a 6-3, 6-0 victory over Fabio Fognini, who won the title in 2019.

Taylor Fritz, the only player to beat Rafael Nadal this year en route to the trophy at Indian Wells last month, overcame home wildcard Lucas Catarina 6-7 (6/8), 7-6 (7/5), 6-4.