The Cottagers have lost their last three Premier League games and sit 19th in the table, two points adrift of safety, but Saints have not won at Craven Cottage since 1947
Not since October 1947 have the south-coast club triumphed at Craven Cottage, with the Londoners winning eight of the 15 games between the two sides at the ground since.
This weekend could provide one of Southampton's best opportunities to bring that record to an end, though, as struggling Fulham languish second-bottom of the Premier League.
Rene Meulensteen's side slumped to their third consecutive top-flight defeat when they were beaten 2-0 at Swansea City on Tuesday.
|23/10||Fulham are 23/10 with Paddy Power to beat Southampton|
Fulham have scored only one goal in their last three games, conceding eight in those fixtures, while no Premier League club have lost more home games this season than their total of seven.
Ninth-placed Southampton have already beaten Fulham once this season, when Rickie Lambert and Jay Rodriguez scored in a 2-0 win at St Mary's in October, head to the capital on the back of a 2-2 home draw with Arsenal.
Meulensteen brought in midfielder William Kvist on loan from Stuttgart for the rest of the season with a view to a permanent move on Thursday.
And the Denmark midfielder hopes to make an immediate impact at the weekend.
He said: "Of course I would like to be involved against Southampton but the head coach will see if I'm fit and able to play - I think I am, although I haven't played for Stuttgart this year, but I'm feeling fit and motivated."
One player who will definitely not feature against Mauricio Pochettino's charges is Adel Taarabt as the playmaker, on loan from QPR, is set to complete a move to AC Milan.
Meulensteen will check on the fitness of John Arne Riise (hamstring) and Fernando Amorebieta (knee), but Matt Briggs (hernia) will not feature.
Pochettino was full of praise for his side following their impressive display against Arsenal and was left to rue not securing all three points.
However, the Argentine is braced for a tough test at Craven Cottage despite Fulham's poor form.
"Fulham will want to get three points from us on Saturday. It's going to be a tough game." Pochettino said.
"There are still a lot of points to be won. Fulham had some problems at the start of the season, but they've changed a lot."
Pochettino revealed that striker Rickie Lambert will return to the squad after recovering from a hamstring problem, and midfielder Victor Wanyama (calf) could start for the first time since early in December.
Striker Pablo Daniel Osvaldo will play no part as he continues to serve a suspension following a training ground incident, while Dejan Lovren and Gaston Ramirez (both ankle) are still not fit.