After Nathan Redmond scored the only goal of the goal at St. Marys' a fortnight ago, The Saints carry a slender goal advantage to Merseyside, as Jurgen Klopp's men look to turn the tie in their favour.
Southampton's Nathan Redmond celebrates scoring their first goal
The Reds will also be looking for a reaction following Saturday's shock 3-2 Premier League defeat to Swansea City - just their third loss of the campaign.
Conversely, Southampton put an end to a four-match losing league streak on Sunday, as Claude Puel's side won convincingly 3-0 on the south coast.
In what is traditionally a competition for the rotation of squads, with a date with destiny on the horizon, both managers are set to throw caution to the wind and name strong line-ups for the clash.
Swansea City's Gylfi Sigurdsson celebrates scoring their third goal with Tom Carroll
Whilst the Saints travel to Merseyside with a new vein of vim, Wednesday's visitors have lost 10 times at Anfield in the modern Premier League era - in all competitions.
They do however hold wins from 2003 and most recently in 2013, when now-Liverpool defender Dejan Lovren scored the only goal of the game in 1-0 win - a goal which was seen as playing a large part in the Croat's move the following summer.
Southampton's Dejan Lovren (C) celebrates scoring his sides first goal with teammates
Jurgen Klopp will be hoping Jordan Henderson shakes a nagging foot injury off for the visit, in Liverpool's only major injury doubt.
Joel Matip having received international clearance from Cameroon, took part in Liverpool's U23s game versus Ipswich Town on Sunday and could feature.
Loris Karius denied the Saints on multiple occasions two weeks ago and is set to be named in goal.
Here is how how Liverpool could line up:
Southampton are sweating on the fitness of both Virgil van Dijk and Steven Davis. Van Dijk was caught on the foot in a tackle by Jamie Vardy on Sunday and was forced to hobble off, whilst the Northern Irishman has a knock.
Should Van Dijk not be passed fit, Jack Stephens is on stand by.
Charlie Austin, Jeremy Pied, Sofiane Boufal, Jake Hesketh and Matt Targett are all ruled out.
Here is how Southampton could line up:
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