Mohamed Salah gave the Reds a glimmer of hope at the Estadio Alfredo Di Stefano, but a Vinicius Junior double and another strike by Marco Asensio might have put Los Blancos out of sight already.
Jurgen Klopp knows that a 2-0 victory will be enough, but given the fact that goals have been uncharacteristically difficult to come by at Anfield this year, that seems like a tough ask.
Liverpool will once again be without their three first-choice centre backs in Virgil van Dijk, Joel Matip and Joe Gomez. That means it will likely be Nat Phillips and Ozan Kabak in front of Alisson in goal and alongside regular fullbacks Andy Robertson and Trent Alexander-Arnold.
Jordan Henderson is still missing in midfield, so expect a trio of Thiago, Gini Wijnaldum, and Fabinho.
Sadio Mane was dropped form the starting XI for the win against Aston Villa at the weekend, so Klopp may opt for a front three of Salah, Roberto Firmino, and Diogo Jota again.
As for Real Madrid, who will be buoyed after the victory over Barcelona on Saturday, there are a number of key players missing.
Sergio Ramos and Raphael Varane are both out, while Dani Carvajal is unlikely to feature. Eden Hazard is still suffering from an ankle problem, too.
Casemiro's red card at the weekend shouldn't stop him from featuring here, but Lucas Vazquez is out for the season. That means Alvaro Odriozola will start at right-back alongside Nacho, Eder Militao and Ferland Mendy.