Injury-ravaged Barcelona could be without seven first-team players as they look to consolidate their position at the top of La Liga at home to Granada on Saturday.
The Catalans will begin a run of eight games across three competitions before Christmas without four-time World Player of the Year Lionel Messi after he tore his left hamstring in Barca's last outing away to Real Betis a fortnight ago.
Barca's injury crisis has deepened since then as goalkeeper Victor Valdes will also miss the rest of the year after rupturing a calf muscle in Spain's 1-0 friendly defeat to South Africa in midweek.
Right-back Dani Alves also returned from international duty with a calf problem that will see him sidelined for up to 10 days, whilst Gerard Pique, Cesc Fabregas and Xavi Hernandez are doubts and Jordi Alba remains out injured.
Valdes' absence means that 38-year-old stopper Jose Manuel Pinto will start in goal for the next six weeks.
And defender Javier Mascherano is confident Pinto's experience will be key in deputising for the on-form Valdes.
"The injuries to Victor and Leo are very important, but every player is able to play," he said on Thursday.
"The squad is very big. Valdes is important for what he represents and for the excellent level he has had until now. But we have to support Pinto, he has always responded when he has needed to.
"He is a keeper with a lot of experience. We cannot forget that he has won two Copa del Reys and had very good performances."
With such a raft of injuries, coach Gerardo Martino may be forced to hand 21-year-old Sergi Roberto his first start of the season in midfield.
Neymar, meanwhile, will carry the significant burden of compensating for the loss of Messi in attack.
Should Barca slip up at the Camp Nou on league duty for the first time in over a year, Real Madrid will be confident of cutting their six-point deficit on the leaders when they travel to Almeria.
Los Blancos will be able to unleash the on-fire Cristiano Ronaldo fresh from his hat-trick that sealed Portugal's place in the World Cup with a 3-2 win over Sweden in midweek.
"It has been a very intense few days with our national teams, but we have two days in front of us to prepare in the best way possible for the next game," Ronaldo told Madrid's website.
"My only goal, like the whole dressing room, is to now work so that all Real Madrid fans continue to be excited by their team."
Ronaldo has also scored nine times in his last four games for Madrid and will look to continue his lethal partnership with Gareth Bale and Karim Benzema in attack.
However, Real suffered a serious injury blow during the international break as Sami Khedira suffered cruciate ligament damage that is likely to keep him out for the rest of the season.
Brazilian midfielder Casemiro is expected to make his first start of the campaign in the German's absence.
Coach Carlo Ancelotti also has a problem at left-back as both Marcelo and Fabio Coentrao are sidelined for the next few weeks through injury.
Second-placed Atletico Madrid are also in action on Saturday as they host Getafe at the Vicente Calderon.
Atleti's top-scorer Diego Costa is not expected to be fit, though, as he is still struggling with the thigh injury that prevented him from making his Spain debut in the world champions' friendly encounters with Equatorial Guinea and South Africa in the past week.
Fixtures (all times GMT)
Valladolid v Osasuna (2000)
Barcelona v Granada (1500), Real Sociedad v Celta Vigo (1700), Almeria v Real Madrid (1900), Atletico Madrid v Getafe (2100)
Levante v Villarreal (1100), Rayo Vallecano v Espanyol (1600), Elche v Valencia (1800), Sevilla v Real Betis (2000)
Malaga v Athletic Bilbao (2100)