Gareth Bale and Luka Modric have been sent to the bench by Zinedine Zidane for a must-win clash against lowly Alaves.
The pair have apparently paid the price for a woeful 1-0 defeat midweek to Betis that leaves the Merengues seven points adrift of Barcelona in La Liga.
With a tough away clash against Borussia Dortmund also on the horizon and numerous injury worries, Zidane's starting line-up takes on an unfamiliar look.
Cristiano Ronaldo starts at centre-forward as the only out-and-out striker in the Madrid side, accompanied by Lucas Vazquez and Marco Asensio.
Dani Ceballos, meanwhile, comes in for Modric after a promising start to his Madrid career, while Nacho continues to deputise for the injured Marcelo.
The hosts come into the game in desperate straits having started the season with five consecutive defeats.
Giovanni Di Biasi will try and stop the rot in his first game in charge of the Basques, and names an unchanged side from the team that went down to Deportivo 1-0 on Wednesday.
Alaves: Pacheco; Vigaray, Maripan, Ely, Duarte; Torres, Manu Garcia; Burgui, Medran, Ibai; Munir.
Substitutes: Romero, Pedraza, Sivera, Alexis, Sobrino, Wakaso, Pina.
Real Madrid: Navas; Carvajal, Ramos, Varane, Nacho; Ceballos, Casemiro, Isco; Vazquez, Ronaldo, Asensio.
Substitutes: Casilla, Llorente, Tejero, Mayoral, Hakimi, Bale, Modric.