The European champions have failed to overcome Atletico in seven games since beating Los Rojiblancos in last season's Champions League final, including last week's 0-0 draw in the first-leg at the Vicente Calderon, and have also been struck by a series of injuries and suspensions to key players.
Luka Modric and Gareth Bale will miss out after limping off with knee and calf injuries respectively in the 3-1 win over Malaga at the weekend, whilst Marcelo is banned and Karim Benzema faces a race against time to be fit due to a knee problem.
Given those absences, the return to fitness and form of James Rodriguez is a huge boost for Los Blancos.
The Colombian World Cup star has scored twice in four games after a two-month injury layoff due to a broken foot to take his tally to an impressive 14 in his first season at the Bernabeu.
"Before I was out I was scoring goals, playing at a good level and now I think it is the same," he told Madrid's website.
"I want to continue like this, using my characteristics to help the team achieve important objectives.
"We are all dreaming of getting through this round and if I can score as well then it would be great. The most important thing is to win and get through this very difficult game, but we are in our own stadium with our own fans. I think it could be a great game."
However, Real will be faced with arguably the best defence in Europe on Wednesday. Atletico have conceded just once in their last eight Champions League games and have shutout their local rivals in four of their previous seven meetings this season.
"Atletico are an intense team that are very good at the back," added Rodriguez.
"There is always pressure. We have to manage it and we are going to do everything we can to win an 11th European Cup."
By contrast, Atletico have a clean bill of health with striker Mario Mandzukic expected to shake off an ongoing ankle problem to start alongside the in-form Antoine Griezmann up front.
Diego Simeone's men remain the underdogs in just their second Champions League quarter-final in 18 years, but midfielder Raul Garcia refuted the suggestion they have less to lose than the holders.
"I don't think we have less pressure. It is the quarter-finals of the Champions League and the two teams want to go through.
"Time will give more value to what we are achieving. Now it seems normal to be in the quarter-finals, to get to the semis would be very important."
Garcia maintained the Atletico party line of recent weeks in insisting there is no thirst for revenge after losing out in heartbreaking circumstances to Real in the Lisbon final last May.
However, he also dismissed the idea that Atletico now have a mental hold over Carlo Ancelotti's men having beaten them over two legs in the Spanish Supercup and the Copa del Rey already this season.
"Lisbon is forgotten. We don't live in the past. We would have loved to have won, but it doesn't change anything. If we had won, we would still want to go through now.
"We have to forget the previous games this year too. They only serve to know that we are doing the right things. We always say the games that have already been played don't matter."
COMMENTS
Comments are moderated and generally will be posted if they are on-topic and not abusive.
For more information, please see our Comments FAQ