Tennis Canada said Thursday Rafael Nadal, ranked No. 3 in the world, is pulling out of the event due to a knee injury.
This will be the first time since his debut appearance in 2004 that Nadal will miss the event in Toronto. He won the tourhament in 2005, as well as three years later.
He also withdrew from the Olympic tennis event in London last week.
Additional draw withdrawals as of Thursday were David Ferrer of Spain, Gael Monfils of France and Spain's Fernando Verdasco.
Nadal says he was planning to play in Toronto and did everything he could to be ready but still needs more time to recover.
"Coming to Toronto is always one of the highlights of my season so I'm very disappointed that I can't play there this year," said Nadal.
Canadian tennis players Frank Dancevic, Vasek Pospisil and Peter Polansky were given wildcards to the men's Rogers Cup.
The three additions to the ATP Tour event at Toronto's Rexall Centre will give Canada four players in the main singles draw.
Milos Raonic of Thornhill, Ont., was already granted automatic entry for his No. 23 world ranking.
Vancouver's Pospisil is the highest ranked of the wildcard players at 85th. Dancevic, from Niagara Falls, Ont., is ranked 135 while Polansky, from Thornhill, is No. 155.
Four Canadians were also given wildcard spots to the qualifying tournament that begins Saturday.
Montreal's Erik Chvojka, Toronto's Steven Diez, Pierre-Ludovic Duclos of Saint-Foy, Que., and Filip Peliwo of North Vancouver, B.C., will play for one of six spots in the main draw.