Kicking off at 8pm UK time, the final round of fixtures sees all 36 clubs in action simultaneously as the battle to reach the knockout stages reaches its conclusion.
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Some teams at the top or bottom, including Arsenal, already know their fate but many still have work to do on what could be a wild evening in Europe's premier club competition.
But how can they secure one of the much-revered top-eight spots on Wednesday evening?
RadioTimes.com breaks down the Champions League 2025/26 qualification permutations for each of the Premier League clubs in the competition.
Arsenal (1st)
v Kairat Almaty (36th) at Emirates Stadium
The Gunners have been the dominant force in the competition this term and are top of the League Phase table with 21 points, having won seven from seven.
A point would guarantee them first place but anything less than a convincing victory against bottom-club Kairat Almaty would be considered a failure for Mikel Arteta's side.
Liverpool (4th)
v Qarabag FK (18th) at Anfield
The Reds are fourth, with 15 points, meaning their fate is in their own hands. A win against Qarabag FK would guarantee them a spot in the top four, which would mean the second leg of their quarter-final, should they make it, is at home.
Qarabag, who are second in the Azerbaijani Premier League, have plenty to play for as they still have work to do to clinch their place in the knockout stages.
Tottenham (5th)
v Eintracht Frankfurt (33rd) at Deutsche Bank Park
Spurs are fifth, on 14 points, meaning a win guarantees them a top-eight finish and could see them rise into the top four should Liverpool or Real Madrid slip up.
The Bundesliga club cannot qualify for the knockout stages and head into Wednesday's game led by interim boss Dennis Schmitt after the recent sacking of Dino Toppmöller.
Newcastle (7th)
v PSG (6th) at Parc des Princes
The Mags are one of eight clubs on 13 points and sit seventh in the League Phase table, thanks to their +10 goal difference.
A point could be enough for both sides, should results elsewhere go their way, but defeat would surely mean Newcastle head into the play-off round – albeit as one of the seeded teams and with the second leg of their tie at St James' Park.
Chelsea (8th)
v Napoli (25th) at Stadio Diego Armando Maradona
A win alone may not be enough for Liam Rosenior's side, who may also be reliant on a goal difference swing.
To make things even trickier for Chelsea, Napoli are 25th in the table and need a result – potentially a draw but ideally a win – to reach the knockout stages.
Man City (11th)
v Galatasaray (17th) at Etihad Stadium
Their place in the knockout stages is secure but Pep Guardiola's side will be desperate to avoid the play-off round, where they were beaten by Real Madrid last season.
There will be some familiar faces in Galatasaray's ranks, with Leroy Sane and Ilkay Gundogan returning to the Etihad. The Turkish club have not yet clinched their place in the knockout stages and need a result if they are to finish as one of the seeded sides.
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