With Karim Benzema joining Gonzalo Higuain on the treatment table, the 27-year-old, normally deployed in an advanced position out wide, will instead lead the line in the absence of any other senior forwards for Jose Mourinho to call upon.
Ronaldo will be supported by an attacking midfield trident of Mesut Ozil, Luka Modric and Jose Callejon, with Xabi Alonso and Sami Khedira taking up their usual deep-lying positions in midfield.
The defence has a more familiar look to it, with regulars Alvaro Arbeloa, Pepe, Sergio Ramos and Fabio Coentrao starting in front of captain Iker Casillas in goal.
Espanyol coach Javier Aguirre faces no such injury concerns and has named an unchanged XI from the side that drew 2-2 against Sevilla last weekend, with goalscorers Verdu and Simao retaining their places in the line-up.
Real Madrid (4-2-3-1): Casillas; Arbeloa, Pepe, Ramos, Coentrao; Alonso, Khedira; Callejon, Ozil, Modric; Ronaldo.
Espanyol (4-2-3-1): Casilla: Víctor Sanchez, Forlin, Sergio, Verdu; Moreno, Javi Lopez; Colotto, Simao, Wakaso; Víctor Álvarez.