Experienced pair Mathieu Bastareaud and Morgan Parra missed out on France's 31-man World Cup squad, head coach Jacques Brunel announced on Tuesday.
Scrumhalf Parra, 30, featured at both the 2011 and 2015 World Cups, but has been suffering from an ankle injury sustained while playing for club side Clermont last month.
Center Bastareaud, also 30, has captained Les Bleus in the absence of regular skipper Guilhem Guirado in recent seasons, and was also a member of the France team that were hammered by New Zealand in the quarter-finals of the 2015 World Cup.
There is also no space for fleet-footed Racing 92 winger Teddy Thomas nor for La Rochelle's giant prop Uini Atonio.
Uncapped front rowers Peato Mauvaka and Emerick Setiano, as well as Fijian-born winger Alivereti Raka, are included in the squad for the first time.
Seven members of Toulouse's Top 14-winning side are named including center Sofiane Guitoune whose last cap came during the 2015 tournament.
Brunel also announced a six-man reserve list as a back-up in case of injuries which includes flanker Francois Cros, who is yet to feature on the international stage.
Les Bleus start their campaign against Argentina on September 21 before facing the USA, Tonga and then England in what promises to be a tough Pool C.
France's 31-man Rugby World Cup squad which takes place in Japan between September 20-November 2:
Forwards (17): Gregory Alldritt, Demba Bamba, Yacouba Camara, Camille Chat, Paul Gabrillagues, Guilhem Guirado, Arthur Iturria, Felix Lambey, Wenceslas Lauret, Bernard Le Roux, Peato Mauvaka, Jefferson Poirot, Louis Picamoles, Dany Priso, Emerick Setiano, Rabah Slimani, Sebastien Vahaamahina
Backs (14): Geoffrey Doumayrou, Antoine Dupont, Gael Fickou, Wesley Fofana, Sofiane Guitoune, Yoann Huget, Camille Lopez, Maxime Machenaud, Maxime Medard, Romain Ntamack, Damian Penaud, Alivereti Raka, Thomas Ramos, Baptiste Serin
Reserves (6): Anthony Belleau, Francois Cros, Etienne Falgoux, Charles Ollivon, Vincent Rattez, Paul Willemse