Napoli will make the trip to the Spanish capital with a different face in the dugout to the one that faced Real on matchday two, as Walter Mazzarri replaced Rudi Garcia, who was sacked over the international duty.
Mazzarri earned a fine away win in his first game back at the club, beating Atalanta in Bergamo on Saturday, and another one here will seal their place in the knockout round alongside their upcoming opponents.
Real also enjoyed a good weekend, returning to the top of La Liga after comfortably seeing off Cadiz 3-0, paired with Girona's failure to beat Athletic Bilbao.
Here, Sports Mole takes an in-depth look at the head-to-head record and previous meetings between the two sides.
Previous meetings: 5
Real Madrid wins: 4
Napoli wins: 1
Napoli have only returned as a major force in the Italian game over the past decade, after years in the wilderness, meaning this will be just their third-ever trip to the Bernabeu.
Real Madrid have not been ideal opponents for the Neapolitans though, as they are still yet to win in five previous meetings, losing on four occasions.
The reverse fixture on matchday two back in October saw Real edge an entertaining encounter 3-2, as a thunderous strike from Federico Valverde, which cannoned off the back of Alex Meret in the Napoli goal, saw Los Blancos claim victory in a game where both sides led inside the first half.
The Partenopei also provided Real Madrid with their first challenge on the way to lifting the Champions League in 2016-17 when they met in the last 16.
Almost all of the 78,000 inside the Bernabeu were left stunned when Lorenzo Insigne scored an incredibly audacious strike from around 40 yards out to put the visitors ahead in the first leg, but Real roared back to win 3-1, thanks to goals from Karim Benzema, Toni Kroos and Casemiro.
The scoreline was repeated in the second leg as Zinedine Zidane led his Real side into the quarter-finals, despite falling behind on the night again thanks to Dries Mertens's 24th-minute goal, but the Belgian went on to put through his own net as Napoli went down 3-1 again.
Back in 1987 when Diego Maradona led Napoli to a first-ever Scudetto, Napoli qualified for a maiden European Cup campaign.
However, standing in their way in the first round were the almighty Real Madrid, and even Maradona's greatness could not inspire Napoli to a win, as a 2-0 first leg defeat in Spain ultimately saw them crash out 3-1 on aggregate.
Napoli have a rather poor record against Spanish opposition in general, winning just two of their previous 13 meetings against La Liga clubs - versus Real Sociedad in 2020 and Granada in 2021 - but the Granada win was in vain as they crashed out of the Europa League last 16 on aggregate on that occasion.
On the other hand, Real have an imperious record against Italian clubs, winning 15 of their last 16, with the only blemish being a defeat at home to Juventus which still saw them progress to the semi-finals in 2018 on aggregate.
Oct 03, 2023: Napoli 2-3 Real Madrid (Champions League Group Stage)
Mar 07, 2017: Napoli 1-3 Real Madrid (Champions League Round of 16 second leg)
Feb 15, 2017: Real Madrid 3-1 Napoli (Champions League Round of 16 first leg)
Sep 30, 1987: Napoli 1-1 Real Madrid (European Cup First Round second leg)
Sep 16, 1987: Real Madrid 2-0 Napoli (European Cup First Round first leg)
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