Manchester City were forced into a major change against Inter Milan which could be crucial ahead of a huge Arsenal match at the weekend.
Kevin de Bruyne was struck by injury just before half-time after an earlier challenge left him crocked.
The Belgian tried to carry on but went down again just before the referee blew up for the first half.
And after receiving treatment in the dressing room, Pep Guardiola made the decision to take him off with Ilkay Gundogan coming on in his place.
Pep Guardiola has a big injury problem on his hands
PA
While the nature of the injury has yet to be disclosed, it is the worst news ahead of their Premier League game against Arsenal on Sunday.
The Gunners have been tipped as City's biggest rivals for the Premier League title this season.
Yet without their talismanic playmaker potentially missing, the task for City might have got much more difficult.
Arsenal have their own problems, with their mercurial midfielder also missing through injury.
Mikel Arteta confirmed that Martin Odegaard had suffered 'significant' ankle ligament damage and could be missing for some time.
It means both teams will be missing crucial players ahead of what is already being sized up as a title showdown.
City have started in perfect fashion in the Premier League after managing four wins out of four.
Arsenal, meanwhile, drew to Brighton before the international break but returned to winning ways with a 1-0 victory over Tottenham in the north London derby at the weekend.
It sees them two points behind Guardiola's men, though there is still a long way to go.
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Kevin de Bruyne was forced off with a groin injury
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De Bruyne's injury came after trying a shot against Yann Sommer in the Inter Milan net before going down.
He held his groin in worrying scenes at the Etihad before eventually being taken off.
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Kevin de Bruyne could miss Man City's match against Arsenal
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The 33-year-old missed a fair chunk of the season last year with a hamstring injury, though City still went on to win the Premier League in his absence.
The former Chelsea star has been linked with a move to Saudi Arabia in recent months and could be an option at the end of the season.
It comes amid frustration with the congested fixture schedule, saying: "We know there will be only three weeks between the Club World Cup final and the first Premier League match. So, we have three weeks to rest and prepare for another 80 matches."
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