Fofana out of French opener
He failed to recover from a groin injury.
The 27-year-old 35-times capped Clermont ace is replaced by Alexandre Dumoulin, who gets another chance despite failing to sparkle in the warm-up Test 19-14 defeat by England on August 15 also at Twickenham.
"We need players who are 100 percent fit on Saturday and Wesley is not," said head coach Philippe Saint-Andre.
"Therefore he is not in the 23-man matchday squad."
Saint-Andre still believes Fofana will be fit for the next Pool D game against Romania on September 23.
Saint-Andre, who will step down at the end of France's campaign, selected the Toulon duo of veteran Freddie Michalak and Sebastien Tillous-Borde at flyhalf and scrumhalf respectively for the third successive game.
Saint-Andre, who has failed to bring more consistency to the France team performances and selection than his predecessor Marc Lievremont managed, said it was imperative the French got off to a good start.
"It is vital we start well," said the 48-year-old former France captain, whose record in charge of the national team since the 2011 World Cup reads a modest 17 wins, two draws and 21 defeats.
"It is important the players do not play the game in their heads before kick-off and its got to be good on the day."
Aside from Italy and Romania the French – who have three times got to the final without lifting the trophy, losing the 2011 edition 7-8 to the All Blacks – will play Canada and round off the pool stage with a potential table-topping decider with Six Nations champions Ireland, who Saint-Andre has yet to overcome in four meetings (two draws and two defeats).
France: 15 Scott Spedding, 14 Yoann Huget, 13 Mathieu Bastareaud, 12 Alexandre Dumoulin, 11 Noa Nakaitaci, 10 Frederic Michalak, 9 Sebastien Tillous-Borde, 8 Louis Picamoles, 7 Damien Chouly, 6 Thierry Dusautoir (captain), 5 Pascal Pape, 4 Yoann Maestri, 3 Rabah Slimani, 2 Guilhem Guirado, 1 Eddy Ben Arous.
Replacements: 16 Benjamin Kayser, 17 Vincent Debaty, 18 Nicolas Mas, 19 Bernard Le Roux, 20 Alexandre Flanquart, 21 Morgan Parra, 22 Remi Tales, 23 Gael Fickou.
Date: Saturday, September 19
Venue: Twickenham, London
Kick-off: 20.00 (19.00 GMT: 21.00 Italian and French Time)
Referee: Craig Joubert (South Africa)
Assistant referees: John Lacey (Ireland), Stuart Berry (South Africa)
TMO: Shaun Veldsman (South Africa)
Agence France-Presse