The gap could be just two points should Manchester City overcome Queens Park Rangers on Tuesday, with Sir Alex Ferguson's side keen to keep a healthy advantage as the season gathers pace.
United have never had more points at this stage of the season (59) than they have registered in 24 games, while their strikers have been full of goals in recent weeks with Wayne Rooney scoring seven in his last eight games, Javier Hernandez five in his last five and Robin van Persie 10 goals in his last 10 league fixtures.
Southampton, meanwhile, have improved in recent weeks. Despite early struggles, they have just lost one of their last five matches in all competitions, a run of form that has moved them into 15th position in the table, ahead of the likes of Newcastle United and Aston Villa. However, they have lost their last five league fixtures at Old Trafford.
Van Persie, Nemanja Vidic, Shinji Kagawa and Rio Ferdinand were all rested for the FA Cup win over Fulham at the weekend and are expected to return. However, the match has come too soon for Jonny Evans and Ashley Young, who will be missing with hamstring and knee injuries respectively.
Southampton, meanwhile, are expected to name the same team that draw with Everton last time out. Vegard Foren is pushing for his debut, but it is unlikely that he will come straight into the team. Meanwhile, skipper Adam Lallana is still struggling with a knee injury.
Manchester United: DWWDW
Manchester United: De Gea; Rafael, Ferdinand, Vidic, Evra; Valencia, Jones, Carrick, Kagawa; Van Persie, Rooney
Southampton: Boruc; Clyne, Yoshida, Hooiveld, Shaw; Schneiderlin, Cork; Puncheon, Ramirez, Guly; Lambert
Sports Mole says: 3-0