World Player of the Year Cristiano Ronaldo returns for a Real Madrid side otherwise stricken by injuries and suspensions as they look to beat Atletico Madrid for the first time in six meetings this season on Saturday.
Ronaldo completed his two-game ban for kicking out at Cordoba defender Edimar as the European champions sneaked past Sevilla to open up a four-point lead over Barcelona at the top of the table on Wednesday.
However, victory came at a cost as World Cup star James Rodriguez broke a bone in his right foot that will keep him out for two months, whilst centre-back Sergio Ramos will also be sidelined due to a hamstring problem in the coming weeks.
Left-back Marcelo misses out at the Calderon too after his appeal against his fifth yellow card of the Liga campaign was dismissed on Thursday.
Real boss Carlo Ancelotti is short of defensive options with Pepe also out with a rib injury, but he insisted he has confidence in the inexperienced pairing of Raphael Varane and Nacho in central defence.
"What we lose above all is experience, but sometimes enthusiasm is a good thing," said Ancelotti.
"The two of them (Varane and Nacho) give me a lot of confidence. Ramos and Pepe are among the best defenders in the world, but I am not worried."
Atletico have bounced back from their heartbreaking Champions League final defeat at the hands of Real last season to beat them in the Spanish Supercup and Copa del Rey over two legs this season, as well as winning 2-1 at the Bernabeu in La Liga earlier in the campaign.
However, defeat this weekend would see them fall 10 points behind the league leaders and all but end their defence of the title.
"I think it is important because the last games against Atletico weren't good, so we have to change this bad run," added Ancelotti.
"It will be a very difficult game, but we want to do something different.
"The motivation is so big for this game being a Madrid derby we don't need the motivation of leaving Atletico 10 points behind."
In contrast to the visitors, Diego Simeone has a fully-fit squad to choose from for the first time since November and defender Diego Godin insisted their desire to beat their cross-city rivals hasn't been diminished by recent success.
"We want to win, we always want to win and even more so against Real Madrid," said the Uruguayan.
"It is a different game and just because we have won the previous games doesn't mean we will win this one.
"We need to prepare well, continue with what we have been doing and that will help us get closer to the result we want."
Barcelona will be eager to capitalise should Real slip up when they travel to face Athletic Bilbao on Sunday.
The Catalans have been in scintillating form since their last visit to the Basque country ended in defeat to Real Sociedad at the beginning of January, winning eight games in a row and scoring 29 goals in the process.
However, they have failed to win in any of their previous three trips to Bilbao, including a 1-0 defeat on their first visit to the new San Mames last season.
Elsewhere, Sevilla, Valencia and Villarreal continue their fight for the fourth and final Champions League place.
Villarreal have the easiest task on paper when they host relegation threatened Granada on Saturday.
Sevilla make their second trip to the capital in five days as they travel to Getafe, whilst Valencia are away to Espanyol on Sunday.
Fixtures (all times GMT)
Saturday
Atletico Madrid v Real Madrid (1500), Villarreal v Granada (1700), Levante v Malaga (1900), Real Sociedad v Celta Vigo (2100)
Sunday
Cordoba v Almeria (1100), Getafe v Sevilla (1600), Espanyol v Valencia (1800), Athletic Bilbao v Barcelona (2000)
Monday
Elche v Rayo Vallecano (1945)
Source: AFP