Nadal, who has not played since retiring injured in the US Open semifinals in September, cited an abdominal injury.
But it is Djokovic who will be top dog when the latest ATP rankings appear on Monday, irrespective of his fate in the French capital this week.
His Bosnian opponent Damir Dzumhur was forced to retire trailing 6-1 2-1, allowing the Serb to extend his sequence of consecutive winning sets to 30, passing his previous best mark of 29 from 2015.
"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", said the 17-time grand slam victor.
"I understand you guys want to go in depth about it, but please respect that I'm in this tournament and I have to focus on every match and try to get as far as I can. As long as I don't feel like I'm taking a chance on my health prior to London (the ATP Tour Finals), that's the key as well", Federer said.
World number one Nadal had been set to face compatriot Fernando Verdasco on Wednesday, but he announced shortly before the scheduled start time that he would not be fit to play.
The 37-year-old Federer is selective of when he plays in order to keep his body as fresh as possible, and he skipped the entire clay-court season for the second straight year.
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Novak Djokovic has stopped play at the Paris Masters to help a struggling spectator.
Federer is coming in hot after winning his 99th career title, in Basel last week.
The 31-year-old has been in top form this week but faces a hard last-eight opponent in Marin Cilic tomorrow. "Of course, I'm very, very happy and proud about it".
"It's going to be a tough one".
Isner beat Mikhail Kukushkin of Kazakhstan 6-3, 6-7 (2), 7-6 (1).
Cilic trailed 5-4 during the tiebreaker but won both points on Dimitrov's serve before serving out the first set.
Fourth-seeded German Alexander Zverev booked his place in the next round with a 6-4 6-4 win over Frances Tiafoe.
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