Russell Martin is missing several key players for the game against Chelsea, who sit third in the Premier League table with five times the number of points Saints have won.
Taylor Harwood-Bellis, Flynn Downes and Tyler Dibling and unavailable through suspension while Lesley Ugochukwu is ineligible against parent club Chelsea.
Southampton have been handed a fitness boost as Martin is confident that Jan Bednarek will make the bench, but will not be ready to start. Here's how we predict Saints will lineup...
Goalkeeper
Alex McCarthy was only fit enough to make the bench at Brighton having played through the defeat against Liverpool thanks to pain-killing injections.
Joe Lumley came in for his Premier League debut and, barring one misplaced pass, gave a good account of himself. He should keep his spot if McCarthy is still struggling.
Defenders
With no Harwood-Bellis and Bednarek, Jack Stephens will be at the centre of defence. Kyle Walker-Peters has played as a centre-half recently and could be partnered by James Bree.
The inclusion of two right-backs in central defence would mean Yukinari Sugawara stays at full-back. Ryan Fraser will likely start on the left.
Midfielders
It is in midfield that Martin has his biggest headache. Moving Ryan Manning into holding midfield, where he played in pre-season, could be the key.
That would free up Mateus Fernandes and Joe Aribo to play in a more advanced role, ensuring some attacking intent.
Forwards
Martin is hopeful that Paul Onuachu will be fit for the game but his update did not fill supporters with confidence that the Nigerian will start.
In the event that Onuachu is not fit enough to start, Adam Armstrong and Cameron Archer should continue their partnership up front.
Full predicted team:
(5-3-2) Lumley; Sugawara, Bree, Stephens, Walker-Peters, Fraser; Manning, Aribo, Fernandes; Archer, Armstrong.