Real take a one-goal advantage into the home leg of this tie, and will hope to book their place in the round of 16 with a comfortable win at the Bernabeu.
But they may have to do so without the services of their star striker.
Mbappe has been dealing with a lingering knee injury since December, but has been playing through it of late due to the magnitude of Real’s recent matches, which included the first leg against Benfica and the Spanish Super Cup final.
According to L’Equipe, though, the problem has caught up with him.
Mbappe appeared in open training on Tuesday, but could not complete the session due to pain in his knee.
After undergoing tests, he has been ruled out of the match against Benfica. It is unclear how long he will remain sidelined.
Mbappe’s absence is a considerable blow for Real. He is Los Blancos’ top scorer this campaign by a considerable distance, his 38 goals in all competitions comfortably eclipsing second-place Vinicius Jr, who has 12.
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"I don't think his problem is scoring goals,” said Alvaro Arbeloa of Mbappe ahead of Wednesday’s match, highlighting his importance to the side. “Not not scoring, not the way he scores them. On the pitch he makes decisions and, if I have to highlight his qualities, he is very intelligent.
“He knows exactly where to move. There will be moments to create chances inside the area and others outside it.
“But Kylian knows very well what he has to do on the pitch and you just have to look at the statistics to understand that he does it well."