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Win and the European champions can close to within five points of leaders Barcelona, who themselves face a tough trip to Villarreal on Sunday night.
Here, AFP Sports looks at five things to look out for in La Liga this weekend.
Madrid's filled fortnight
Zinedine Zidane has just one natural centre-back available in Nacho for Sevilla's visit with Sergio Ramos along with Dani Carvajal and Casemiro suspended, whilst Raphael Varane and Jesus Vallejo are both sidelined by injury.
Madrid have precious little room for error as they jet off to Abu Dhabi for the Club World Cup straight after the game and could therefore lose even more ground on their rivals who will be in league action next weekend.
In the worst case scenario, Real could start the Clasico 14 points behind Barca with no realistic hope of retaining their title.
Can Sevilla move on from N'Zonzi?
For that to happen, though, Sevilla would need to win at the Bernabeu for the first time since 2008.
The Andalusians will also not be at full strength with a row between Steven N'Zonzi and the club meaning the French international has been left out of the squad for the last four games.
N'Zonzi claimed earlier this week his time at Sevilla was "over" and the saga overshadowed the Andalusians sealing their place in the Champions League last 16 on Wednesday.
Without N'Zonzi there is a huge reliance on Guido Pizarro to keep the likes of Isco and Luka Modric quiet and ensure Ever Banega gets enough of the ball to continue his fantastic form of late.
Bakambu test for makeshift Barca
A Barca defence shorn of the injured Samuel Umtiti and Javier Mascherano will have to turn to Thomas Vermaelen to face one of La Liga's more fearsome strike forces this weekend in Villarreal's Carlos Bacca and Cedric Bakambu.
Only Lionel Messi has scored more than Bakambu's nine goals in La Liga this season.
Vermaelen has made just 13 La Liga appearances in four years since joining from Arsenal due to a series of injury setbacks and a failed loan spell at Roma with Barca's intention to look for centre-back cover in January saying much for their confidence in the Belgian.
Setien's last stand?
Real Betis' brilliant start to life under Quique Setien, which included a win at the Bernabeu in September, has quickly disintegrated.
One league win in eight games allied to an embarrassing 5-3 home defeat to second division Cadiz in the Copa del Rey means Setien, who was also coveted by Valencia in the summer, is now clinging onto his job.
A revitalised Atletico Madrid could inflict the final blow as they look to bounce back from their disappointment at bowing out of the Champions League in midweek by moving to within three points of the top.
Another graveyard shift for Espanyol
For the fifth time in eight home games this season, Espanyol have been shunted into playing on a Friday or Monday night when they host Girona in a Catalan derby.
The harsh scheduling has been disastrous for Espanyol's numbers through the turnstiles as just under 12,000 attended their last Monday outing against Getafe on November 27, the worst ever attendance for the 40,500 capacity stadium.
A banner drapped across the 70 percent empty stands that night read: "Black Monday: stands at thirty percent" as supporters' resistence to La Liga president Javier Tebas's insistence that every match be shown at a separate kick-off time for television rises.
Fixtures (all times GMT)
Friday
Alaves v Las Palmas (2000)
Saturday
Getafe v Eibar (1200), Real Madrid v Sevilla (1515), Deportivo la Coruna v Leganes (1730), Valencia v Celta Vigo (1945)
Sunday
Real Sociedad v Malaga (1100), Real Betis v Atletico Madrid (1515), Levante v Athletic Bilbao (1730), Villarreal v Barcelona (1945)
Monday
Espanyol v Girona (2000)
