Cristiano Ronaldo and Gareth Bale will both miss Real Madrid's clash with Leganes on Wednesday, the club have announced.
There is a full card of Spanish top-flight fixtures this midweek, with Zinedine Zidane's men forced to respond to Barcelona, who play Sevilla at home earlier in the day.
However, the current league leaders, who could be second in the standings by the time they start, will be without two key figures in the form of Ronaldo and Bale, both of whom have failed to make the cut for their squad.
Zidane has elected to give two of his star attacking players a break, while he has also left Toni Kroos out of the party that will make the short trip to the south-west of the capital.
Meanwhile, the only injury problem that Madrid are forced to tackle ahead of this encounter is France international centre-back Raphael Varane, who limped out of Saturday's victory over Deportivo Alaves prematurely.
Neither Bale nor Ronaldo was on target in that encounter but both played the full 90 minutes. Karim Benzema, who did score, however, was substituted in the closing 10 minutes and is liable to shoulder much of the attacking burden at Butarque.
Nevertheless, the coach hinted the Portuguese is in excellent shape during his pre-match press conference. "I think he is going to finish the season like never before," he explained.
"Well, I never know because he also ended other years very well, but he's very good physically and I hope he will end [the season] very well."
Zidane's decision to allow some of his most important players to sit out the game reflects a busy period for the capital outfit, who are fighting tooth and nail with Barca to reclaim the Spanish crown, while also seeking to become the first club in the Champions League era to retain the title of European Cup holders. To that end, Madrid tackle Bayern Munich in seven days, though the French coach's thinking is probably towards the weekend, when his men will play another derby match, this time against Atletico Madrid.
With two big games on the horizon, it would appear that he feels he can shuffle his pack to face opponents who are five points but only one place above the relegation zone.