Rafael Nadal has pulled out of the Paris Masters with an abdominal injury, meaning Novak Djokovic is guaranteed a return to world No 1 on Monday.
The Spaniard was due to play his first match since his US Open semi-final retirement against Juan Martin del Potro but withdrew shortly before his second-round meeting with Fernando Verdasco.
Nadal arrived at the final regular tournament of the season targeting his 34th Masters 1000 title and needed to match Djokovic's performance to remain at the summit of the men's rankings.
Djokovic, who defeated Joao Sousa on Tuesday, will become the first player to go from being ranked outside the world's top 20 to No 1 in the same season since Marat Safin in 2000.
It is unclear whether Nadal will be able to feature at the season-ending ATP Finals in London, live on Sky Sports, next month.
"My abdominal muscles haven't felt good for the past few days, especially on service, doctors recommended that I didn't play," Nadal said.
The 32-year-old was forced to retire injured against Marin Cilic in the Australian Open quarter-finals and has missed events in Beijing and Shanghai since his retirement at Flushing Meadows in September.
"It's been a difficult year for me in terms of injuries, and so I'd prefer to avoid doing anything drastic," he added.
"It wouldn't have been good for me nor anyone to return to the court knowing that I wouldn't be able to play my best."
Lucky loser Malek Jaziri took full advantage of Nadal's withdrawal as the world No 55 from Tunisia defeated Verdasco 7-6 (7-5) 1-6 6-3 in two hours and twenty six minutes.
Milos Raonic also withdrew from the tournament, citing a right elbow injury, which handed Roger Federer a walkover to the last 16.
The 20-time Grand Slam champion, playing in the event for the first time since 2015, will now meet Fabio Fognini on Thursday, after the Italian 13th seed also benefited from a withdrawal by Marton Fucsovics.
Defending champion Jack Sock defeated France's Richard Gasquet 6-3 6-3 to record only his eighth victory of the season and will next meet the winner between Verdasco and Jaziri.
Fourth seed Alexander Zverev reached the last 16 with a 6-4 6-4 win against Frances Tiafoe, which featured six breaks of serve.
John Isner - one of four players in contention for the two remaining singles spots in the season finale at the O2 - hit 33 aces in a three-set encounter against Mikhail Kukushkin.
The American wasted four break points in the second set as he was pushed the distance by his world No 54 opponent before he dominated a final set tiebreak to progress 6-3 6-7 (2-7) 7-6 (7-1).
Kevin Anderson, who won the Erste Bank Open last week, continued his strong end-of-season form with a 6-3 6-7 (3-7) 7-6 (7-3) win against Nikoloz Basilashvili.
The seventh seed saved all three break points he faced in the match and will next face Kei Nishikori in a repeat of their Vienna final after the Japanese player opened the day's schedule with a 7-5 6-4 success against France's Adrian Mannarino.
Nishikori needs to reach the Paris semi-finals to make his fourth appearance in the eight-man field at the ATP Finals.
Grigor Dimitrov, who has Andre Agassi working with him this week, also progressed to the last 16 with a hard fought 7-6 (12-10) 6-4 victory against Roberto Bautista Agut.
"He [Agassi] is amazing. I couldn't think of a better guy, sharing thoughts, feelings, emotions, on and off the court," said Dimitrov, who is coached full-time by Dani Vallverdu.
"I just believe that he has gone through so much overall with the ups and downs and all that. He's one of the only people that I feel I can really relate to and open up to."
He added: "Hopefully I can travel with Andre a bit more next year, and for sure we're going to try to spend a lot more time together in the upcoming weekends and months.
"Hopefully in the next couple of months we'll know more about how we're going to do our schedule."
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