Atleti suffered a setback in their quest for a first top-flight crown since 1996 last weekend as they fell to a 3-0 defeat at Osasuna.
Fellow title chasers Barcelona also succumbed to defeat at the hands of Real Sociedad, leaving Carlo Ancelotti's men three points clear at the end of the weekend.
But, with 13 matches left to play, all three will still be harbouring hopes of laying claim to the trophy come May.
For Atleti, the first of those fixtures is a home clash with Real, and coach Diego Simeone will be desperate not to allow Ancelotti's side to pull six points clear.
The teams have met on three occasions already this season, with Real currently leading by two wins to one, but a series of unsavoury events in recent fixtures adds even more spice to this encounter.
Sergio Ramos spitting at Diego Costa, Cristiano Ronaldo being struck by a lighter, and Marcelo's allegations of racism against opposition fans are all incidents that have happened in fixtures between the sides over the past two seasons.
Victory for Simeone's charges would see them climb above Real, having also beaten their rivals 1-0 in the reverse fixture back in September.
Barcelona will bid to recover from their 3-1 defeat to Sociedad in a home tie against lowly Almeria.
The Camp Nou outfit can feel confident of a return to winning ways after putting 21 goals past their opponents in the last five meetings, conceding just one in reply.
At the other end of the table, Real Betis will bid to bring a three-match losing run to an end at Villarreal, while Rayo Vallecano host eighth-placed Valencia.
Real Valladolid are without a win in four, but could climb out of the relegation zone with victory over Malaga, who would themselves drop into the bottom three.
Elsewhere, Athletic Bilbao host Granada to kick off the weekend programme on Friday, Espanyol travel to Getafe, and Celta Vigo are the visitors at Elche.
Osasuna and Sociedad will look to follow up their shock victories last time out with triumphs at Levante and Sevilla respectively.
‘The pure simplicity of the way Slot has managed the squad is probably the biggest thing I could say about him. It’s not broken, so let’s get on with it’: Liverpool legend full of admiration for Jurgen Klopp's successor at Anfield
‘I trained at Spurs and thought they’d give me a chance. But I received a letter thanking me but saying they didn’t think I was good enough – I was gutted’: How Tottenham missed out on signing Wales legend John Toshack
