Eden Hazard will miss El Clasico on December 18 after Real Madrid confirmed he has suffered a small fracture in his ankle.
Hazard was forced off in the 2-2 Champions League draw with Paris Saint-Germain late last month and required help as he hobbled off the pitch.
Coach Zinedine Zidane expressed concern after the match, convinced it was "more than a simple blow", only for initial scans to suggest Hazard had just suffered bruising.
But media reports suggested there was growing concern with Hazard's condition as he was still requiring the use of crutches to walk.
Madrid subsequently sent Hazard for further tests and discovered "an incomplete external microfissure" – or small fracture.
While the club have not confirmed how long they expect him to be absent for, such injuries generally take at least a month to recover from, with widespread media reports adamant Hazard will miss El Clasico.
Madrid are due to face Barca at Camp Nou on December 18, with the match rescheduled after the initial contest on October 26 was postponed due to political unrest in Catalonia.
Marcelo is also in doubt for the match after Madrid confirmed he is suffering with a calf injury.
While the issue is not thought to be as serious as Hazard's, Madrid-based publication Marca claim he could be out for three weeks.
Madrid and Barca are tied on 31 points from 14 matches in LaLiga, one ahead of Sevilla and former Blancos coach Julen Lopetegui, who have played 15 games.
Ahead of El Clasico, Madrid face Espanyol and Valencia domestically, while they will also go to Club Brugge in the Champions League.