Tournament organisers in Paris announced on Wednesday that Nadal had pulled out due to an abdominal strain.
After Rafael Nadal's withdrawal from Paris on Wednesday, Novak Djokovic has secured the number 1 spot in the rankings next Monday, becoming world number 1 for the first time since October 2016 after an incredible run since Rome and especially since Wimbledon where he won the title to announce a great comeback.
Nadal who has not played since retiring injured in the U.S. Open semi-finals, withdrew because of injury.
Novak Djokovic has spoken of his pride at a "highly improbable" return to the top of the ATP rankings.
The Wimbledon and US Open champion led Damir Dzumhur 6-1 2-1 when the Bosnian was forced to retire because of injury.
"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've played him many, many times and we practise a lot.
If he wins that, against Kei Nishikori, he could face Novak Djokovic in the semifinals - but Federer is thinking more about winning the season-ending ATP Finals, which start November 11.
As a result of Nadal's withdrawal, Djokovic will be confirmed as the new world number one on Monday.
Serbia's Novak Djokovic returns the ball to Portugal's Joao Sousa during their men's singles second round match on day two of the ATP World Tour Masters 1000-Rolex Paris Masters-indoor tennis tournament at The Accor Hotels Arena in Paris, on October 30, 2018.
Despite the blow the tournament organizers will be relieved to see Roger Federer making his first appearance at the competition since 2015.
He added: "I am going to fight as strong as I can to win as many matches as possible". "I'll give it a go [on Wednesday]".
"I feel like it's better for me to play matches rather than practice", Federer said.
The 37-year-old Swiss had only made a late decision to compete in Bercy after winning his 99th title in his home town Basel on Sunday but, despite a touch of raggedness, was sharp enough to outclass the Italian 6-4, 6-3 in his opening match.
Having suffered a shock defeat to Marco Cecchinato in the quarter-finals of the previous month's French Open, Djokovic looked back to his brilliant best on Centre Court.
Fourth seed Alexander Zverev has booked a second round berth at the Paris masters after beating Francis Tiafoe.
Isner beat Mikhail Kukushkin of Kazakhstan 6-3, 6-7 (2), 7-6 (1).