James has been brought back into the fold by Zinedine Zidane this season after spending two years on loan at Bayern Munich.
The Colombia playmaker - who suffered a calf strain earlier in the campaign - has made nine appearances in all competitions, starting five times, though last featured for Zidane's side in a Champions League victory over Galatasaray on October 22.
Parte médico de James Rodríguez. #RealMadrid— Real Madrid C.F.⚽ (@realmadrid) November 18, 2019
However, James could now be set to miss up to six weeks after Madrid announced the 28-year-old has sprained a ligament in his left knee.
Madrid's statement, released on the club's official website, did not place a timeframe on James' recovery, stating the midfielder would continue to be assessed.
Los Blancos face rivals Barca - who currently lead LaLiga on goal difference - on December 18 in the rearranged Clasico at Camp Nou, which was postponed due to political unrest in Catalonia.