The Reds have already eased to victory over Bologna and AC Milan in this year's new-look competition, but their Bundesliga hosts are yet to pick up a point.
Match preview
Arne Slot's Liverpool revolution is showing no signs of slowing down anytime soon, as the Reds passed one of the stiffest tests of their Premier League title credentials yet on Sunday, when the Dutchman won the battle of the newly-baptised Premier League bosses with Enzo Maresca.
A clinical Mohamed Salah penalty and scuffed Curtis Jones effort ensured that Nicolas Jackson's fine finish would be scant consolation for Chelsea, as Liverpool re-established their one-point lead over Manchester City at the Premier League summit and made it 10 wins from 11 under Slot's wing.
Two of those successes have come against Italian opposition in Europe, as Liverpool followed up their 3-1 beating of AC Milan with a 2-0 triumph over Bologna on matchday two, even if they did ride their luck at times and were fortunate that the Rossoblu had left their shooting boots behind.
Sterner examinations are to come - Sunday's trip to title rivals Arsenal has all the makings of a blockbuster battle - but the Merseyside powerhouses, who sit fifth in the 36-team UCL table, are currently riding cloud nine as they chase an eighth successive victory in all competitions.
What is more, the Reds have won all five of their away games under Slot thus far - keeping three clean sheets and only giving up two goals in the process - and not since the 2001-02 season have Liverpool been beaten by a German side on the road in the Champions League.
That sequence includes a 2-0 triumph over Leipzig at the Red Bull Arena in February 2021, when Klopp was in the Liverpool dugout, but the German will soon be assisting operations for Wednesday's hosts instead after agreeing to become Red Bull's new Global Head of Soccer from January.
Marco Rose's side could do with some European inspiration from the 2019 Champions League winner right now, though, as their 2024-25 record reads two defeats from two European games, even if they were against some titanic foes in Atletico Madrid and Juventus.
Die Roten Bullen managed to keep both contests close - only losing to a last-minute Jose Gimenez goal versus Atletico - but they led a one-goal lead slip on two occasions against 10-man Juventus, falling 3-2 to the Dusan Vlahovic-inspired Bianconeri.
On that evening, Juve lost key defender Bremer to injury after just seven minutes and saw goalkeeper Michele Di Gregorio sent off approaching the final 30, but they still managed to strike twice more with a numerical disadvantage as Leipzig suffered a truly calamitous collapse.
Things have been looking slightly rosier for Rose's side since - they have posted back-to-back Bundesliga wins against Mainz 05 and Heidenheim with two clean sheets to boot - but they could now become the first team to ever lose three straight Champions League games despite scoring the opening goal in all of them.
RB Leipzig Champions League form:
L
L
RB Leipzig form (all competitions):
L
D
W
L
W
W
Liverpool Champions League form:
W
W
Liverpool form (all competitions):
W
W
W
W
W
W
Team News
Liverpool's triumph over Chelsea came at a bit of a cost, as Diogo Jota lasted just half an hour before succumbing to the effects of a Tosin Adarabioyo challenge, and Slot would be surprised to see the Portugal international make the cut on Wednesday.
Alisson Becker (hamstring) and Harvey Elliott (foot) are also taking up places in the infirmary, while the luckless Federico Chiesa remains a doubt, and young right-back Conor Bradley was also missing from the matchday squad against Liverpool for unexplained reasons.
Bradley's omission almost put Slot in a right-back crisis, as the Dutchman revealed that Trent Alexander-Arnold was also a doubt before the game, so Joe Gomez may earn an unexpected start in defence if the Liverpool boss protects Alexander-Arnold before the Arsenal affair.
Rose can empathise with Slot over fresh attacking concerns, as Leipzig lost top scorer Lois Openda to a knock in the closing stages of the Mainz victory, but the Belgian played down his issue after the game and insisted that he would be fine for Wednesday.
The same goes for Amadou Haidara, who also suffered an injury scare in the second half of the weekend's win, but Xaver Schlager (ACL), David Raum (ligament), Nicolas Seiwald (groin) and Assan Ouedraogo (knee) are all in the care of the doctors.
Assuming his knock does not flare up, Openda will form part of a menacing-looking front three alongside Xavi Simons and Benjamin Sesko, who has scored all three of Leipzig's goals in the Champions League so far.
RB Leipzig possible starting lineup:
Gulacsi; Orban, Klostermann, Lukeba; Geertruida, Haidara, Vermeeren, Nusa; Simons; Sesko, Openda
Liverpool possible starting lineup:
Kelleher; Gomez, Konate, Van Dijk, Tsimikas; Mac Allister, Gravenberch; Salah, Jones, Diaz; Nunez
We say: RB Leipzig 1-2 Liverpool
Leipzig appear to have shored up defensively since the Juventus capitulation, although Liverpool are a different kettle of fish to Mainz and Heidenheim, and the Reds have our vote to make it 11 from 12 under Slot.