Kaka, Marcelo and Arbeloa out of Lyon clash
The trio were not included in the Spanish club's 20-man squad for the Group D clash due to minor muscle injuries.
Brazil playmaker Kaka has a bruised calf, his compatriot Marcelo is suffering from a thigh problem and Arbeloa has an injured thigh.
"It's a bit curious because I had planned to rest them a bit against Real Sociedad. Marcelo is unfortunately out although he did not play in San Sebastian," coach Jose Mourinho told a news conference on Tuesday.
"Kaka played only 15-20 minutes but he took a lot of knocks. I knew it would be complicated for Kaka but it's more of a surprise for Marcelo."
Mourinho said that Raul Albiol would play in defence and will wear a mask to protect his face after he suffered an injury during a training session with the Spanish national team last month.
Real, who crushed Lyon 4-0 at home two weeks ago, will qualify for the first knockout round if they win at Stade de Gerland.
Lyon have injury problems of their own with defender Aly Cissokho "very doubtful" with a thigh injury, according to coach Remi Garde.