Arne Slot's men are aiming to make it three wins out of three in the 2024-25 edition, having seen off two Serie A foes in the shape of AC Milan (3-1) and Bologna (2-0) in their first two European affairs of the season.
On the other hand, Leipzig have been defeated by both Atletico Madrid and Juventus, failing to hang onto a one-goal lead on both occasions, and they could now become the first side in Champions League history to lose three consecutive games that they have taken the lead in.
Here, Sports Mole takes an in-depth look at the head-to-head record and previous meetings between the two sides.
Head-to-head record
Previous meetings: 2
RB Leipzig wins: 0
Draws: 0
Liverpool wins: 2
With Leipzig only becoming a dominant force of German football in the past decade, the head-to-head history in this fixture is very modest indeed, with only two previous competitive contests on the record books.
Those matches came in the 2020-21 Champions League last 16, both played behind closed doors as coronavirus raged across Europe, and Jurgen Klopp's side schooled their Red Bull counterparts on both occasions.
Indeed, Klopp - who will soon help out at Leipzig as Red Bull's new Global Head of Soccer - masterminded a 4-0 aggregate victory over Julian Nagelsmann's men, following up a 2-0 success in Germany with an identical triumph at Anfield.
The inaugural meeting between Leipzig and Liverpool in February 2021 saw Mohamed Salah and Sadio Mane strike after half time for the Reds, who took on Die Roten Bullen in the midst of their defensive injury crisis; Jordan Henderson and Ozan Kabak played at centre-back that day.
Three weeks later, Liverpool eased into the quarter-finals of Europe's top competition with another 2-0 win inside a near-empty Anfield, but again, they failed to register in the first half of the contest.
As well as an identical scoreline, the second leg also saw identical scorers, as Salah broke the deadlock a few minutes before Mane made sure of the result for Liverpool, who would go on to lose to Real Madrid in the quarter-finals.
Leipzig and Liverpool have locked horns since that two-legged European tie, albeit in an exhibition match best erased from the Germans' memory banks, as the Reds thrashed Die Roten Bullen 5-0 in a summer 2022 friendly.
Salah was customarily on target against Leipzig in that encounter, but the other four goals were all scored by the same man - Darwin Nunez - who should get the chance to replicate that astonishing feat on Wednesday thanks to Diogo Jota's injury.
Previous meetings
Mar 10, 2021: Liverpool 2-0 RB Leipzig (Champions League Round of 16)
Feb 16, 2021: RB Leipzig 0-2 Liverpool (Champions League Round of 16)
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