After being handed the initiative once again due to Manchester City's draw with QPR, Manchester United can open up a seven point gap with a home win against the Saints.
In for a real baptism of fire, Mauricio Pochettino's first away game in English football couldn't be tougher. Despite drawing his first game as manager, Southampton overall are unbeaten in their last six games.
Robin Van Persie is set for a re-call into the starting line-up after being rested for the comfortable FA Cup win against Fulham on Saturday. Defensive pairing, Nemanja Vidic and Rio Ferdinand are also expected to return. Ashely Young and Jonny Evans will miss out due to injuries.
Adam Lallanna could make his first appearance in almost two months, after being sidelined as a result of knee ligament damage. New signing Vegard Forren is available to make his debut. Jose Fonte and Guly Do Prado are both ruled out with knee injuries.
KICK-OFF: Wednesday 8pm
PAST THREE MEETINGS…
Southampton 2 (Lambert, Schneiderlin) Manchester United 3 (Van Persie 3) Premier League, September 2012
Southampton 1 (Chaplow) Manchester United 2 (Owen, Hernandez), FA Cup, January 2011
Southampton 0 Manchester United 3 (Welbeck, Nani, Gibson) FA Cup, January 2009
Manchester United are in rich vein of form, winning 26 points from a possible 30, eight win and two draws from their last ten.
Southampton striker Rickie Lambert leads the way in goalscoring for the Saints this season with ten goals. He needs two more to reach the landmark of 100 goals in all competitions for the club.
This is the first time the two sides will be playing at Old Trafford since December 2004, the previous five games (league and cup) have all been played at St Mary's.
Southampton's last league win at Old Trafford was in January 1988, back in the Old First Division.
Manchester United to win: 1.22
Southampton to win: 13.0
These two sides played out a memorable 3-3 draw at Old Trafford back in September 1999. While a remarkable scoreline, the match is best remembered because of goalkeeper Massimo Taibi's howler from Matt Le Tissier's tame effort. The blunder effectively ended the Italian's career at United.
TV: Highlights - BBC1 at 10.35pm