Bayern Munich winger Franck Ribery has been ruled out of France's World Cup campaign, along with Lyon midfielder Clement Grenier.
Montpellier's Remy Cabella and Southampton's Morgan Schneiderlin will replace the duo, whose absence was announced by Didier Deschamps at a press conference in Clairefontaine ahead of his side's departure to Brazil.
Ribery had been following an individual training programme to overcome a back problem and failed to prove his fitness after rejoining the full squad on Friday. Grenier sat out the session as he underwent scans on a thigh injury, and both players' worst fears were confirmed by coach Deschamps.
Deschamps said in the press conference screened on the French Football Federation's official website: "(Ribery) stopped with a strong pain.
"He had tests early in the afternoon which unfortunately confirmed the severity of the situation, that he will be unavailable for several weeks."
Grenier missed much of Lyon's Ligue 1 run-in with a separate injury and, having regained his fitness in time to join up with France, the latest setback has cost him his trip to the tournament.
"He had a groin problem with his club but he participated in the last match," said Deschamps.
"He came with us and participated in the training sessions and in the match against Norway. On Wednesday he trained as normal, Thursday morning as well, but on Thursday afternoon in the game, he suffered a terrible blow and felt pain in his right adductor.
"He had an MRI scan, which unfortunately again confirmed he will be incapacitated for several weeks, he will not be able to train or, evidently, to play.
"We submitted to FIFA the two medical documents and we decided to call up Morgan Schneiderlin and Remy Cabella.
"The two players were on the reserve list and they are similar to the two players who left us. You cannot copy them exactly but Morgan Schneiderlin is the player most in the profile of Clement Grenier, and Remy Cabella is the most in the profile of Franck Ribery."
Lyon forward Alexandre Lacazette and midfielder Maxime Gonalons were also included in the seven-strong reserve list which also featured defenders Loic Perrin and Benoit Tremoulinas.
St Etienne goalkeeper Stephane Ruffier had already been called up in place of Marseille's Steve Mandanda, meaning Deschamps has now been forced to make three changes to his original squad.
Deschamps admitted Ribery's absence, in particular, is a major setback but vowed not to lose heart ahead of the tournament.
He said: "We know what Franck is capable of. With Franck Ribery at 100 per cent, we are better.
"But we have to be ambitious and we will continue to be."
For Ribery, it marks the end of his World Cup career if a recent interview he gave to radio station RTL is to be believed.
"It will be my last World Cup," he said on May 21. "We have to go there to achieve something, to try to win the World Cup, quite simply."
The 31-year-old made his international breakthrough by helping Les Bleus to the 2006 final in Germany, where they lost on penalties to Italy.
But he was also part of the wretched 2010 campaign in South Africa which ended in mutiny as, following a dispute between then coach Raymond Domenech and striker Nicolas Anelka, the team refused to train and captain Patrice Evra was seen arguing with fitness coach Robert Duverne.
Ribery was reported to have clashed with fellow midfielder Yoann Gourcuff following France's defeat to Mexico, but made an extraordinary unscheduled appearance on TV station Telefoot to dismiss those claims, express his sorrow for France's under-performance and support Domenech's authority.
It would have been a first World Cup for Grenier, who has won five caps for Les Bleus since making his debut against Uruguay last year.
The 23-year-old earned international recognition after establishing himself as a key figure with Lyon.
He made 36 appearances for the club last season, recording six goals and five assists, and turned down a move to Newcastle in January as the Magpies sought a replacement for departed France star Yohan Cabaye.
Both he and Ribery appeared on the official squad photo published earlier on Friday by the FFF but Cabella will now take Ribery's number seven shirt, with Schneiderlin taking over from Grenier at number 22.
Cabella made his senior France debut as a 79th-minute substitute in last Tuesday's 4-0 friendly win over Norway, after 17 caps and four goals at under-21 level.
The uncapped Schneiderlin has spent six years at Southampton and has played in the top three divisions of the English league.
He began his career with Strasbourg and has won three under-21 caps and five for the under-20 side, scoring once at each level.