Arsenal forwards Theo Walcott, fresh from his hat-trick heroics at the weekend, and Alex Oxlade-Chamberlain, are likely to start at St Mary's, as Arsenal look to regain their place in the top four of the Premier League.
Their former club, however, look likely to return to the Championship, languishing in the relegation zone and without a win in three games. After being denied three points on Saturday by Cameron Jerome's late equaliser for Stoke, the Saints may be more determined to stun the visitors.
The trio of Łukasz Fabiański, Abou Diaby and Andre Santos, after Arsenal's 7-3 win over Newcastle, are likely to be absent again. A knee injury to Southampton midfielder Adam Lallana, meanwhile, has kept him out of action since 8 December.
KICK-OFF: Tuesday, 5:15pm
PAST THREE MEETINGS...
Arsenal 6 (Hooiveld OG, Podolski, Gervinho 2, Clyne OG, Walcott) 1 Southampton (Fox), Premier League, September 2012
Southampton 1 (Crouch) Arsenal 1 (Ljungberg), Premier League, February 2005
Arsenal 2 (Henry, Van Persie) Southampton 2 (Delap 2), Premier League, October 2004
Southampton are without a win against the Gunners since 2002, with a 3-2 league victory at St Mary's.
Former Saints player Theo Walcott's hat-trick against Newcastle on Saturday was his third for Arsenal, and second of 2012.
Southampton have the fewest clean sheets in the league (two).
Walcott now has 14 goals for the season, one more than his previous record – 13 from 38 games in 2010-11 – and 62 minutes per goal involvement.
Southampton to win: 4.8
Arsenal to win: 1.75
TV: Live on Sky Sports 1 HD at 5:15 pm, highlights on BBC1 at 10.25pm