Karim Benzema has been ruled out of World Cup 2022 in Qatar after tearing a muscle in his left thigh, the French Football Federation has confirmed.
The Ballon d'Or winner, 34, was forced to leave defending champions France's training session early after suffering the injury in training on Saturday.
"Karim Benzema is out of the World Cup," the French football federation (FFF) said.
"After hurting the quadriceps on his left thigh the Real Madrid striker is forced to give up on taking part in the World Cup."
Benzema was taking part in his first full training session with Les Bleus when he had to come off after feeling some pain in his left thigh.
"He went for an MRI scan in a hospital (clinic) in Doha, which unfortunately confirmed a tear," the FFF added.
Benzema wrote on Instagram: "In my life I have never given up but tonight I have to think about the team, as I have always done, so reason tells me to leave my place to someone who can help our group make a good World Cup.
"Thank you for all your messages of support."
France coach Didier Deschamps added: "I am extremely sad for Karim who had made this World Cup a major objective. Despite this new blow for the French team, I have full confidence in my group. We will do everything to meet the huge challenge that awaits us."
Since winning the Ballon d'Or last month, Benzema has played fewer than 30 minutes for Madrid after coming off the bench in a Champions League game against Celtic.
Benzema was France's top scorer at the 2014 World Cup but did not play in France's victorious 2018 World Cup campaign. France coach Deschamps recalled him for last year's European Championship, where he was France's top scorer with four goals.
Forward Christopher Nkunku was injured just minutes before the end of the team's previous training session on Tuesday evening and has since been replaced in the squad by Randal Kolo Muani.
Deschamps is already missing midfielders Paul Pogba and N'Golo Kante, who helped France win the World Cup four years ago.
Pogba injured his knee in pre-season and underwent surgery in September to repair a damaged meniscus. The 29-year-old resumed training before his agent confirmed the midfielder would not return to action for Juventus or France before the World Cup.
Chelsea midfielder Kante suffered a setback in his rehabilitation from a hamstring injury that has restricted him to two league appearances this season. He will be sidelined for four months after undergoing surgery.
Deschamps also has an anxious wait to see if his best central defender, Raphael Varane, is fit to face Australia - exactly a month since he limped off for Manchester United with a hamstring injury.
Fellow World Cup winner and central defender Presnel Kimpembe pulled out of the France squad on Monday after failing to sufficiently recover from a six-week layoff following a hamstring injury.
Even without Benzema, France still have a strong attack to face Australia. They are likely to start with Olivier Giroud as the central striker, flanked by 2018 World Cup star Kylian Mbappe and either Barcelona's Ousmane Dembele or veteran Antoine Griezmann.
Giroud has scored 49 goals for France, Griezmann has 42 and the 23-year-old Mbappe already has 28. Dembele has been in fine form for Spanish league leaders Barcelona this season.
Deschamps has until Monday - the eve of the Australia game - to call up a replacement for Benzema to his 26-player squad. Monaco striker Wissam Ben Yedder, who has three international goals, could provide an option.
Les Bleus are in action against Denmark four days later and before they take on Tunisia on November 30.