Their opponents: another London club in West Ham, who are currently ravaged with injury after a good start to life under Croatian boss Slaven Bilic.
West Ham will be missing the likes of Manuel Lanzini, Victor Moses, Dimitri Payet, Winston Reid and Diafra Sakho through injury, while Aaron Cresswell, James Tomkins and Andy Carroll could return depending on late fitness tests.
Like on Boxing Day, Southampton will likely miss Graziano Pelle and Cedric Soares to knee and groin injuries respectively. Meanwhile, long-term absentees Florin Gardos, Jay Rodriguez and Fraser Forster remain injured.
The last three Premier League games between the two sides at Upton Park have produced 13 goals.
Southampton are looking to win consecutive away games away at West Ham for the first time since 1992.
West Ham are unbeaten in six matches at home after losing their first two.
The Hammers have only conceded two goals in their last five matches - even with their injury problems.
Southampton striker Shane Long has scored five and assisted two goals in his last seven Premier League starts for Southampton.
Bet Victor: West Ham: 12/5 - Draw: 12/5 - Southampton: 13/10
Bet 365: West Ham: 9/4 - Draw: 12/5 - Southampton: 11/8
How to Watch:
Date/time: 28/12/2015, 17:45 UTC (UK) - 12:45 ET (USA)
Venue: Upton Park, London, UK
TV: None (UK), NBCSN (USA)
Streaming: None (UK), NBCSN (USA)
Radio: BBC Radio Solent (UK), TalkSport (UK)