Both Morocco's Amine Harit and Poland's Bartlomiej Dragowski could even miss the rest of their club seasons after picking up horrifying damage a week before the tournament starts.
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Attacking midfielder Harit, who is one of Morocco's most talented players, went down after an hour of his Marseille side's 3-2 Ligue 1 win over Monaco and looked in serious trouble.
Replays and stills from a collision with Axel Disasi showed his kneecap clearly dislodged, leaving one teammate 'disgusted'.
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Marseille captain Valentin Rongier said: "We are obviously very affected, and we hope it won't be too serious.
"We saw without seeing too much, and afterwards we tried to protect him. He looked sad and worried. Now we wait. I'm disgusted, afterwards, it was hard to get back into the game."
Manager Igor Tudor added: "From what we know, it's a very big injury. He got injured just before the World Cup, we talked about it all week, I'm very sad."
It's since been confirmed by OM that the player suffered a cruciate ligament sprain and will be out of the tournament.
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In the lead up to the match, Harit discussed potential injuries ahead of the tournament, saying it would be 'fate' to pick up a serious issue.
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"From the moment you start to calculate, to be careful not to hurt yourself, that's when the injuries happen," he said.
"You have to play as if it were a normal match, and it's by giving your all that you avoid injuries. You have to go into the duels at 100 per cent and not think about the World Cup.
"The World Cup, if we play, so much the better, if we get hurt in the last match, it's fate, that's what was planned. But there will be no restraint."
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There were similarly horrifying scenes for Poland's Dragowski, whose Spezia teammates were left shocked on the bench to see his foot facing the wrong direction.
The goalkeeper left the field in tears before half-time in Spezia's 2-1 Serie A win over Hellas Verona.
The shot-stopper was battling former Arsenal man Wojciech Szczesny for the number one spot in Poland's goal, but will now be out indefinitely after his club announced he avoided a fracture, but dislocated his ankle which needs to be stabilised.
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Poland have since called up a replacement.
Poland will begin their World Cup campaign against Mexico on November 22, while Morocco kick off their tournament against Croatia a day later.