Manchester United will get a glimpse of life after Edwin van der Sar as they travel to the south coast dealing with a defensive shortage.
Sir Alex Ferguson has confirmed that Van der Sar will not make the trip, although he is not injured, missing a game only two days after it was announced this will be the 40-year-old's final season.
Recent signing Anders Lindegaard could make his debut, although no final decision has been made, and whichever goalkeeper does play will have to do so behind a makeshift defence, with Rio Ferdinand (groin), Patrice Evra (family bereavement), and Rafael da Silva (concussion) all out.
Midfielder Michael Carrick is also doubtful with an ankle injury.
Southampton will check on Dean Hammond and Adam Lallana.
Skipper Hammond has been sidelined since he limped out of the third-round win over Blackpool with a calf problem and fellow midfielder Lallana has missed the last two matches with a knee injury.
The duo are edging closer to fitness and boss Nigel Adkins will make late decisions on them.
Adkins this week signed Dany N'Guessan on loan from Leicester and the winger is eligible to make his debut against the Premier League giants.
Lee Holmes is a long-term absentee as he recovers from ankle surgery and fellow wideman Jason Puncheon appears to have fallen out of favour again.
Manchester United (from): Kuszczak, Lindegaard, O'Shea, Brown, Neville, Vidic, Smalling, Evans, Fabio, Nani, Obertan, Carrick, Fletcher, Scholes, Gibson, Anderson, Giggs, Bebe, Rooney, Berbatov, Hernandez, Owen.