Southampton can move three points clear of ninth-placed West Brom with victory over Manchester United at St Mary's on 17 May.
Where to watch live
Kick-off is set for 7.45pm BST. The game will be broadcast live on Sky Sports 1 HD.
Jay Rodriguez and Nathan Redmond scored as Southampton bounced back from their defeat against Arsenal to beat Middlesbrough 2-0 at the Riverside on 13 May. The Saints were beaten 2-0 by Manchester United in the reverse fixture at Old Trafford in August, with Zlatan Ibrahimovic scoring both goals.
Virgil van Dijk and Alex McCarthy are sidelined through injury for the hosts.
Manchester United's winless run extended to three matches as they fell to a 2-1 defeat against Tottenham in the last ever game at White Hart Lane on 14 May. The Red Devils beat Southampton 3-2 in the final of the EFL Cup at Wembley in February.
Midfielder Paul Pogba will miss the trip to the south coast after the death of his father, but Marouane Fellaini is available after serving a ban.
What managers say
Claude Puel: "The last result away against Middlesbrough allowed us the possibility to finish strong in the Premier League. A lot of people ask me what the possibilities are for this team, and it's about having a good focus about the game [on Wednesday], not having to focus on relegation, Europa League games or different things, and I'm happy with all the work we can do on the pitch and in the training sessions." [via BBC]
Jose Mourinho: "Now it's time to play two good games to close the Premier League and reach the Europa League final in the best shape that we can. It's true that the calendar has been hectic over the last two months, but we have to push hard now to try to win the three remaining games. We really want to." [via BBC]
- Southampton: WLDDL
- Last result: Middlesbrough 1-2 Southampton
- Manchester United (all competitions): LDLWL
- Last result: Tottenham Hotspur 2-1 Manchester United
Betting odds (Betfair)
- Southampton win: 17/10
- Draw: 23/10
- Manchester United win: 19/10
Southampton possible XI: Forster; Pied, Caceres, Yoshida, Bertrand; Clasie, Davis, Romeu; Rodriguez, Austin, Redmond
Manchester United possible XI: Romero; Valencia, Bailly, Jones, Darmian; Fellaini, Herrera; Mkhitaryan, Rooney, McTominay; Rashford