Carlo Ancelotti's men arrive at their headquarters with a 1-0 lead from the first leg three weeks ago, hardly an unassailable advantage for their Bundesliga counterparts to make up.
Match preview
As Jude Bellingham took his spot on the sidelines due to an ankle injury, his lieutenant Brahim Diaz lit up the Red Bull Arena with a sensational solo effort to settle the first leg of their last-16 showdown, weaving his way through Leipzig legs and finding the top corner with panache.
Ancelotti's troops still conceded several opportunities to their attack-minded hosts - most of which fell at the feet of Benjamin Sesko - but a combination of Roten Bullen wastefulness, last-ditch defending and Andriy Lunin heroics saw Los Blancos head home with a narrow advantage.
In the three weeks that have followed, however, Real have only won one of their subsequent three La Liga matches, playing out a 1-1 draw with Rayo Vallecano and edging past Sevilla 1-0 before refereeing controversy reared its ugly head in Saturday's tie with Valencia, where Los Blancos came from 2-0 down to rescue a point.
Bellingham thought that he had snatched victory from the jaws of defeat for Real Madrid with a last-gasp header, but Gil Manzano's whistle had blown just as Diaz sent his cross into the box, leading to almighty Blancos protests at the full-time whistle in which Bellingham saw red for something he said towards the referee.
Reeling from that "unprecedented" decision, albeit still seven points clear of Girona at the summit of the La Liga standings, Real Madrid now seek to avoid just a second exit from 21 Champions League ties in which they have won the first leg; their only previous such elimination came versus Ajax in the 2018-19 last 16.
On that occasion, Erik ten Hag's troops recovered from a one-goal home deficit with a phenomenal 4-1 Bernabeu beating, and RB Leipzig must now emulate their Eredivisie counterparts if they are to prolong their Champions League journey at the expense of the tournament's most successful side.
Marco Rose's men could and probably should have found a way past the Blancos backline at the Red Bull Arena on February 13, only to be let down by a missing clinical edge, but Die Roten Bullen had no trouble putting their chances away in a 4-1 Bundesliga thrashing of VfL Bochum at the weekend.
After Peter Gulacsi let a seventh-minute Maximilian Wittek free kick slip through his grasp, he was bailed out by Dani Olmo, Lois Openda, Yussuf Poulsen and an Ivan Ordets own goal, although Leipzig are still playing catch-up in the top-four race owing to an underwhelming streak of winter form.
Victory at Bochum was just a third win from 10 competitive games for Rose's side, who sit one point behind Borussia Dortmund in fifth place in the Bundesliga standings and head to the Bernabeu having failed to win any of their last six Champions League knockout games - a sequence stretching all the way back to 2019-20.
A third last-16 exit in four seasons awaits the German upstarts should their Bernabeu comeback mission end in failure, and on their only previous trip to Real Madrid's turf in the 2022-23 group stage, they succumbed to second-half strikes from Federico Valverde and Marco Asensio in a 2-0 loss.
Real Madrid Champions League form:
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Real Madrid form (all competitions):
D
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D
RB Leipzig Champions League form:
L
W
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RB Leipzig form (all competitions):
W
D
L
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W
Team News
While Bellingham is facing a reprimand domestically for his sending-off against Valencia - Ancelotti argued that the Englishman did not actually insult Manzano and merely used the F-word - he is fine to line up against Leipzig, although he is one booking away from a Champions League ban.
Eduardo Camavinga is in the same boat but is a nailed-on starter regardless, and Ancelotti's only three injury concerns for the second leg are ACL victims David Alaba, Thibaut Courtois and Eder Militao, the latter two of whom are on track to return next month.
Following the publication of a video on social media, La Liga authorities are now investigating alleged racist abuse from a child towards Vinicius during Real's draw with Valencia, less than a year on from similarly despicable incidents at Mestalla.
As for RB Leipzig, head coach Rose will be forced into an alteration due to suspension, as French defender Mohamed Simakan was booked for the third time in the tournament in the first leg and must sit out the trip to the Spanish capital.
Simakan started on the bench against Bochum anyway, and with Lukas Klostermann - Leipzig's only injury victim - still working his way back from a hip concern, Castello Lukeba and Willi Orban should form an untouched defensive barrier in front of Gulacsi, only just back from an abdominal strain himself.
Midfield fulcrum Xaver Schlager returns from a Bundesliga suspension of his own, though, and the Austria international should earn an immediate midfield recall over countryman Nicolas Seiwald.
Netting his 17th Bundesliga goal of the season as a substitute in the thrashing of Bochum, hotshot Openda is primed to displace Christoph Baumgartner to partner Sesko, who missed three big chances in the first-leg loss to Ancelotti's team.
Real Madrid possible starting lineup:
Lunin; Carvajal, Tchouameni, Rudiger, Mendy; Valverde, Camavinga, Kroos; Bellingham; Rodrygo, Vinicius Jr
RB Leipzig possible starting lineup:
Gulacsi; Henrichs, Orban, Lukeba, Raum; Olmo, Haidara, Schlager, Simons; Openda, Sesko
We say: Real Madrid 3-1 RB Leipzig (Real Madrid win 4-1 on aggregate)
The writing is normally on the wall for Real Madrid's opponents after Los Blancos have won the first leg of a Champions League knockout tie, and Wednesday should be no different given Leipzig's indifferent run of form since the turn of the year.