Sunday's blockbuster at Camp Nou offers Madrid the opportunity to open up a nine-point advantage over bitter rival Barcelona at the top of LaLiga.
Madrid recorded a 7-1 win at Cultural in the first leg without their star attacker and coach Zinedine Zidane confirmed he will once again be missing in the return fixture at the Santiago Bernabeu.
"Wednesday's (local time) game is a chance for Ronaldo to have some rest," Zidane said.
Nevertheless, the Madrid coach was adamant that they will not take the match lightly, before confirming that Casemiro will make his comeback after a two-month lay-off due to a fractured leg.
"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," he added.
"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."