Atletico's top scorer Antoine Griezmann and Real captain Sergio Ramos facing a race against time to be fit.
Madrid: Atletico Madrid host Real Madrid for the last time in La Liga at the Vicente Calderon on Saturday with the pain of a second Champions League final defeat in three years to their city rivals still fresh in the memory.
However, both sides have been troubled by severe injury problems with Atletico's top scorer Antoine Griezmann and Real captain Sergio Ramos facing a race against time to be fit.
Real lifted their 11th European Cup on penalties in the last meeting between the teams in May and Atletico are the more desperate side for more reasons than just revenge as Diego Simeone's men lie six points off the leaders at the top of the table.
"There are scars that remain there and that we will never forget," said Atletico captain Gabi.
"They are bitter moments and above all they are hard because of what it meant to all Atletico fans."
Atletico are due to move to their new La Peineta stadium next season after 50 years at the Calderon.
"That it is the last derby at the Calderon in La Liga makes it all the more exciting and special," added Gabi.
"If we win we are in the fight once more."
Griezmann returned from international duty with France with a severely bruised left foot, but has trained this week and is expected to start.
Real are even more ravaged by injury with Pepe, Toni Kroos, Casemiro and Alvaro Morata definitely sidelined.
Ramos hasn't played since spraining knee ligaments over a month ago, but Real boss Zinedine Zidane is hoping he will hold together a leaky Real defence that has kept just one clean sheet in 11 games despite a 28-game unbeaten run in all competitions.
"He is our captain and it is a joy to see him with us once more," said Zidane.
"We know how important he is and that he is on the field is very important for the group."
Despite Real's European hoodoo over Atletico, it is the red and white side of Madrid that has dominated in recent seasons in league encounters.
Atletico haven't lost a league derby in the past three seasons, including Zidane's only La Liga defeat as Real boss in a 1-0 win at the Santiago Bernabeu back in February.
With their two major title rivals facing off, Barcelona have the chance to jump into top spot earlier on Saturday when Malaga visit the Camp Nou.
Barca reversed a trend of poor results following international breaks with a 4-0 hammering of Deportivo la Coruna last month, but once again face being deprived of some of their South American stars.
Luis Suarez is suspended, whilst Lionel Messi and Neymar only arrived back in Barcelona on Thursday after starring for Argentina and Brazil respectively in World Cup qualifying.
Paco Alcacer will start in Suarez's absence as he continues his search for a first Barca goal since a 30 million euro move from Valencia in August.
"Tomorrow he will start and what I would most like is that his objective is not to score, but that the team wins," said Barca boss Luis Enrique.
"The objective should be the same as the rest of his teammates."
Meanwhile, Barca should be boosted by the return of Gerard Pique and Jordi Alba from injury.
Sevilla will aim to remain in the title hunt and bounce back from a thrilling 2-1 defeat to Barca a fortnight ago when they visit Deportivo la Coruna.
Two sides will also be under new management for the first time as Victor Sanchez takes charge of Betis at home to Las Palmas and Joaquin Caparros's bow as Osasuna coach comes on Monday at Leganes.