Benzema was originally named in Didier Deschamps' squad but the striker picked up an injury in training ahead of the tournament, ruling him out.
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The Ballon D'Or winner instead watched from home as his teammates went within touching distance of retaining their world title in Qatar.
And Benzema, who was not part of the 2018 World Cup winning side, has now ended his career with France after making 97 appearances.
He posted on Twitter saying: "I made the effort and the mistakes it took to be where I am today and I'm proud of it!
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"I have written my story and ours is ending."
Why has Benzema retired from international football?
Benzema has had a torrid time in international football and his retirement does not come as much of a surprise after he experienced years of disappointment.
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The striker was a regular for Les Bleus up until 2015 when he was exiled from the squad following a blackmail case involving former teammate Mathieu Valbuena.
Despite many appeals for his call-up, he was left out of Euro 2016 by Deschamps and the former French FA president Noel Le Graet would come out to say that Benzema's 'adventure with France was over.'
He then responded to the claim by saying: "If you think that I am finished, let me play for a country that I am eligible to play for and we will see."
This led to a long separation between the player and his country and he would continue to miss out on international call-ups.
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He was not part of France's World Cup triumph in 2018 with the relationship still struggling.
However, after six years of exile, Deschamps and Benzema were able to overcome their past issues and he was called up for the first time since October 2015 for Euro 2020.
Deschamps commented on his inclusion of the striker after such a long disagreement. He said: "Everyone can make mistakes.
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"I have already had difficult relationships with some players, but this shirt is above everything else. I took the time to think, to analyse my feelings. My job is not to surprise.
"I never said that Karim was not eligible for France. We can't go back in time. The most important is that we saw each other. I needed it, and he did too."
Benzema would join a front line of Kylian Mbappe and Antoine Griezmann but Les Bleus would not experience success.
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They were knocked out by Switzerland on penalties in the round of 16 despite their frightening attack.
He would continue to make appearances in his rejuvenated international career and after winning the Ballon D'Or last season, he was in perfect form for a World Cup.
But after getting the opportunity to lead the line for France in Qatar, his dreams were shattered after he picked up an injury in training.
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He was unable to play in any of the competition as Les Bleus made it to the final yet again, with Deschamps publicly ruling out his return despite Benzema returning to training with Real Madrid.
A replacement for the 35-year-old was not called up, meaning he was still registered and could have been involved in the final if France wanted.
Benzema posted a cryptic message on Instagram on Friday - a selfie with the words "I don't care" as the caption.
Reports in Spain reported in the build-up that Benzema was 'outraged' with Deschamps over his decision, and even that the striker was 'asked to leave' the France camp following his injury.
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Madrid-based newspaper Libertad also claim Benzema recovered from his injury quickly, but was never offered a route back into the team, as Deschamps apparently 'does not want him'.
In his absence, France would go on to lose to Lionel Messi and Argentina on penalties following a thrilling 3-3 draw.
Benzema turned down an invite to the final from French President in a move that has reportedly led to more discontent.
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The striker has now announced his retirement and his international career has come to an end in a way that sums up his disappointing time with France.