Leaders Barcelona host Granada on Saturday hoping to avoid another dose of the "FIFA virus", the dip in form they have often suffered in their first match back after an international break.
In their two La Liga outings immediately following their players' return from country duty this season, Barca needed a last-gasp Alexis Sanchez goal to scrape past Sevilla 3-2 in September and were held to a 0-0 draw at Osasuna last month, the only points they have dropped in 13 matches.
Their task against eighth-placed Granada has been complicated by a rash of injuries to key performers, including world player of the year Lionel Messi, playmaker Xavi and goalkeeper Victor Valdes.
Messi is unlikely to play again before mid-January, Xavi is a doubt for Saturday and Valdes, who has made a host of crucial saves this season, is out for around six weeks.
"I am sad that I cannot help my team mates at the moment but it's an injury that will heal normally and I will return next year full of desire to get going again," Messi said in an interview with Marca sports daily published on Thursday.
Coach Gerardo Martino will be looking to Brazil forward Neymar to shoulder some of the burden of scoring and creating goals in Messi's absence, while Chile forward Alexis has been in fine form for club and country in recent weeks.
Barca are three points clear of second-placed Atletico Madrid, who host city rivals Getafe on Saturday (2100), after Real Madrid, a further three points back in third, play at promoted Almeria (1900).
Real's Portugal forward Cristiano Ronaldo, La Liga's top scorer with 16 goals, is on a high after his brilliant hat-trick against Sweden on Tuesday secured his country's place at next year's World Cup finals in Brazil.
The 28-year-old is close to unstoppable on current form but Real coach Carlo Ancelotti also has injury problems to deal with, especially in defence.
Ronaldo's Portugal team mate Fabio Coentrao was hurt in the Sweden game, while fellow left back Marcelo has not played since damaging his knee in training on Nov. 8 and is not due back for another couple of weeks.
Ancelotti will also have to shuffle his midfield after regular starter Sami Khedira tore knee ligaments playing for Germany last week and has been ruled out for six months.
Playmaker Isco, who started the season strongly but has faded in recent weeks, could come in to play behind Real's formidable attacking trident of Ronaldo, Karim Benzema and record signing Gareth Bale, Ancelotti said this week.
Atletico have emerged as a genuine third force alongside wealthy Real and Barca, at least for the time being, but face a stiff test against Getafe, who have out-performed this term and are sixth.
Atletico coach Diego Simeone, whose nickname is "Cholo", has infected his players with the same fighting spirit he showed as a combative midfielder and Messi had warm words of praise for his Argentine compatriot in Marca.
"Some thought they wouldn't be able to maintain the rhythm but carrying on from the end of last season they are still fighting on all fronts," he added.
Fourth-placed Villarreal, seven points adrift of Real, play at mid-table Levante Sunday (1100).