Following on from their 1-0 win on Saturday, Ronald Koeman's men travel up to Stoke to play the Staffordshire club for the second time in five days as both teams look to advance to the Capital One Cup quarter-finals stage.
Southampton are yet to play at home in this competition, following tough away wins at Millwall and Arsenal. Stoke have had an easier ride, having overcome Sunderland and Portsmouth to reach the fourth round.
Saints made it to the fourth round last year, succumbing to defeat up at eventual finalists Sunderland, so they will be looking to go one better this time around.
Mark Hughes' Stoke side will have had a good look at Southampton after their 1-0 loss at St. Mary's on Saturday. Sadio Mané was the difference on the weekend, scoring Saints' solo goal. However, Koeman yesterday said Senegalese star Mané could be an injury doubt for tonight's game.
Other than that, there are no fresh injury concerns with the likes of Jay Rodriguez and James Ward-Prowse still sidelined with injury. Hughes may make a few alterations to his Stoke starting XI following Saturday's game:
"We may have to make changes because there were a few bumps and bruises [on Saturday].
"I've got other guys that are chomping at the bit to be a part of what we're trying to do this year... so we'll have to look to see if we can give them an opportunity to impress on Wednesday."
Koeman has played a strong team throughout the competition so far. It's expected Saints will play a similar squad to Saturday, though it is likely Matt Targett and Shane Long will get a start tonight.
Prediction: Stoke 1-1 Southampton (Southampton win on penalties)