Rafael Nadal pulled out of the Paris Masters before his quarter-final with a knee injury on Friday which could also rule the 16-time Grand Slam champion out of the season-ending World Tour Finals.
World number one Nadal, who has suffered from knee and wrist injuries throughout his career, decided to withdraw on Friday morning after having his right knee strapped during his third-round win over Pablo Cuevas.
He did not say if he would be fit for the Tour Finals in London later this month.
"For me it's not about London. For me it's about longer term," the 31-year-old, whose withdrawal allowed Serbian qualifier Filip Krajinovic to reach the semi-finals, told a press conference.
"Yesterday (Thursday), the pain was very strong but it was not the moment to stop.
"I had treatment last night to try and be able to play today... But unfortunately it was impossible for me to return to the court in the same condition as last night. It is a sad day for me."
Nadal has fought back this year from a series of injuries, winning the French and US Open titles.
He became the oldest man to secure the top spot in the end of season rankings when he beat Hyeon Chung in his opening match on Wednesday.
"I'm going to do my treatment, do my best to be playing in London, but I cannot talk about that now because (it) is a day that is tough enough for me to pull out from here," he added.
Tournament director Guy Forget was not so sure Nadal would be fit in less than two weeks' time.
"I believe he's quite sceptical about his chances of playing in London now, and he came to Paris all the same," Forget said.
Isner two wins from London
Meanwhile, ninth seed John Isner ended Juan Martin del Potro's World Tour Finals hopes with a 6-4, 6-7 (5/7), 6-4 victory.
Isner will qualify ahead of Spaniard Pablo Carreno Busta for the season-ending eight-man event in London if he lifts the title in the French capital on Sunday.
Last year's runner-up Isner will face Krajinovic in Saturday's semi-finals.
"That's very, very unfortunate for Rafa, and I suppose for the fans here as well," Isner said.
"My opponent came through qualifying so has won five matches already and is playing really well. I just need to play my game and see what happens."
Isner's compatriot Jack Sock can also snatch a ticket to London with tournament victory in Paris, and he takes on Fernando Verdasco in the last quarter-final later on Friday.
Del Potro struggled to find his best form as a run of 25 matches since the start of the US Open in August caught up with him.
"I'm sad of course, I was close to qualifying," he said.
"But at the same time, a few weeks ago I didn't expect to be in this position at all.
"I'm exhausted, I gave it everything. In the third set, I didn't have much left in my legs."
Del Potro faltered at the key moment in the 10th game of the opener and Isner claimed a one-set advantage by putting away a forehand volley.
The second set went to a tie-break, and Isner double-faulted to send the match into a decider.
But Del Potro appeared to be struggling with his fitness, and was broken early in the third set after Isner successfully challenged a line call when 40-15 down.
The 32-year-old served out the match, helped by his 15th ace, to continue his bid for a maiden Masters title.
Krajinovic, 25, will play his first ATP semi-final of the season against Isner, having spent most of 2017 on the second-tier Challenger Tour.
"I did not expect this at all, I was ready to play but then I heard he had pulled out," he said.
"I'm going to enjoy today and then see how it goes tomorrow (Saturday)."