Rafael Nadal has withdrawn from the Paris Masters with an abdominal injury.
It means Novak Djokovic, 31, will replace him as world number one when the rankings are released on Monday.
The Serb will lead the rankings for the first time in two years, with Briton Andy Murray having taken top spot from him in Paris in November 2016.
Earlier on Wednesday, world number three Roger Federer made it through to the last 16 without playing when Milos Raonic pulled out with an elbow injury.
Djokovic, a 14-time Grand Slam champion, was ranked 21st going into this year’s Wimbledon and will become the first player to be outside the world’s top 20 and the world number one in the same season since Russia’s Marat Safin in 2000.
Spaniard Nadal, 32, was due to make his comeback after nearly two months out with a knee injury that led to him retiring from his US Open semi-final.
“I felt better than I thought I would one week ago but in the last few days I started to feel a bit in my abdominal, especially when I was serving,” the French Open champion said.
“I checked with the doctor and the doctor recommended that I did not play.
“It has been a tough year for me in terms of injury so I want to avoid drastic things.
“I have to think longer term. I want to keep playing tennis for a couple of years, so I have to do the logical thing.”
The Spaniard has not made any decisions yet about whether he will play at the season-ending ATP Finals in London in November.
Nadal’s scheduled Paris opponent, 34-year-old Fernando Verdasco, will play Jack Sock in the next round after the American beat France’s Richard Gasquet 6-3 6-3.
The matches which did happen…
Earlier, Kei Nishikori had a straightforward 7-5 6-4 victory over Adrian Mannarino and John Isner served up 33 aces as he beat Mikhail Kukushkin 6-3 6-7 (2-7) 7-6 (7-1).
Japanese 28-year-old Nishikori did not face a single break point as he defeated home crowd favourite Mannarino in one hour and 27 minutes to progress.
He will meet seventh seed Kevin Anderson or Georgian Nikoloz Basilashvili in the next round.
On Court One, Isner’s powerful serving ensured he was not broken at all but wasted opportunities meant he struggled to get past Kazakh Kukushkin.
The American’s serve only let him down at the second-set tie-break, as the world number 54 forced a deciding set.
That went the distance too but this was a different story for Isner, who won early points against the Kazakh’s serve to take the match.
Isner needs to reach the semi-finals in Paris to have any hope of moving up to ninth in the rankings, which would give him a chance of making the ATP Finals.
Later on Wednesday, Alexander Zverev beat Frenchman Frances Tiafoe 6-4 6-4.
The pair traded missed break points in first set before the German, 21, won the final game on Tiafoe’s serve.
In the second set, Zverev broke three times but was broken twice as he wrapped up the eventful match in one hour and 44 minutes.
Ninth seed Grigor Dimitrov is also through after beating Roberto Bautista Agut 7-6 (12-10) 6-4.
BBC tennis correspondent Russell Fuller
There is, as ever, huge sympathy for Nadal, who has this year missed nine events for a combination of ailments, and pulled out of a Grand Slam quarter-final and semi-final.
He always does everything he can to compete at London’s end-of-season ATP Finals, as he is acutely aware of how many he has missed. Last year he played through pain against David Goffin, before withdrawing from the tournament. Maybe this year he would be better to rest.
Two years ago here in Paris, Djokovic lost to Marin Cilic in the quarter-finals and Andy Murray took the opportunity to replace him as world number one.
The Serb’s return to the top is a remarkable achievement when you consider his stunning defeat by Marco Cecchinato in the French Open quarter-finals.
Djokovic then went hiking in the mountains with his wife Jelena, which seemed to clear his head. The world number 21 heading into Wimbledon, he has only lost once since and seems almost certain to be year-end number one for a fifth time.