The former Manchester United star has been in fine form this season, leading his team to the top of the La Liga table.
Winger Gareth Bale is already on the treatment table following an ankle injury but Zinedine Zidane is happy to trust his fringe players for Wednesday’s clash.
Madrid won 7-1 in their first leg against Cultural without Ronaldo and with El Clasico on the horizon this weekend, Zidane admits the Portuguese star will get a few days rest.
With Ronaldo out, several members of the squad will get the chance to play and Brazilian Casemiro is back after a broken leg.
Zidane told reporters: “Wednesday’s game is a chance for Ronaldo to have some rest.
“It is true that 7-1 is a very good result for us, but we must respect the opponent, and the fans who come to support us.
“I hold Cultural in high esteem. They are a good team that can cause us problems.
“Casemiro will get minutes. It will be his first game back, so we will have to see and see how he feels for Saturday’s match. But he is ready to play.”
Southampton have announced plans for a two-week tour of China as part of their pre-season preparations for the 2018-19 season.