It will be the seventh meeting between the two fierce rivals in 2014 and both may feel they have a score to settle, with Atleti having taken the domestic honours last season while Real completed 'La Decima' with an extra-time triumph in the UEFA Champions League final.
Indeed, there have already been two Madrid derbies this season, with Atleti coming out on top 2-1 on aggregate in the Supercopa de Espana.
For Diego Simeone's charges to be competing so closely with their illustrious and big-spending neighbours is an achievement in itself, and that reality is not lost on Atleti defender Juanfran.
"We will never have excessive confidence, not against Real or against anyone," he said in quotes reported by AS.
"The derby matches are closer nowadays than they used to be, since we ended our run of defeats."
Atleti, who responded to their disappointing opening-game draw with Rayo Vallecano by beating Eibar 2-1 last time out, suffered a blow ahead of the Real showdown after Cristian Rodriguez sustained a calf injury.
The winger was withdrawn after just 24 minutes of Uruguay's 1-0 win over South Korea on Monday and is a major doubt for the trip to the Santiago Bernabeu.
Cristiano Ronaldo's absence was keenly felt by his country as Portugal suffered a shock 1-0 loss to Albania in Euro 2016 qualifying on Sunday, but the prolific Ballon d'Or holder has been training for Real and should feature.
Sami Khedira, however, has undergone knee surgery and will definitely miss out.
Carlo Ancelotti's side will be seeking a response to the 4-2 defeat against Real Sociedad before the international break.
Real surrendered a two-goal lead in that match and will be wary of a visiting side who won 1-0 at the Bernabeu in last season's Liga meeting.
Diego Costa, who has since left for Chelsea, grabbed the winner on that occasion.
Simeone's men went on to finish just three points ahead of Real as they won their first league crown in 18 years.
With such fine margins separating champions and also-rans, this weekend's game could have a big say in who gets domestic bragging rights this term.
