Manchester City, who have fallen eight points behind United and now have a near impossible task of regaining the lead they held in the title race for five months, are at home to West Bromwich Albion.
The only thing certain thing about that match is that disgraced Italian Mario Balotelli will not be playing for City after being sent off in the defeat at Arsenal on Sunday with his coach Roberto Mancini saying he will probably sell him once the season is over.
Arsenal, meanwhile, can firm up their grip on third place if they inflict a sixth successive defeat on relegation-bound and bottom-placed Wolverhampton Wanderers at Molineux.
The night's other match sees two of last season's promoted sides, Queens Park Rangers and Swansea City, meet at Loftus Road with QPR still battling against an immediate return to the Championship and mid-table Swansea looking ahead to a second season in the Premier League.
With six matches to play United have 79 points, City 71 and third placed Arsenal are on 61, two clear of Tottenham Hotspur and Newcastle United.
Even allowing for Wigan's recent improvement which has seen them unbeaten in seven of their last nine matches, Roberto Martinez's side are still one from bottom and deep in trouble one off the bottom of the table.
Wigan have also lost all of their 13 previous League meetings against United since they first met in the 2005/06 season with that dismal run including six successive home league defeats.
United also beat Wigan 5-0 at Old Trafford in December and their last five matches have produced a goal tally of 21-0 in United's favour. With United in blistering form having won their last eight League games and 11 of their last 12, Wigan would create the upset of the season with a victory.
United winger Ryan Giggs, on course for an unprecedented 13th League championship medal as United chase a 20th title, told United's website that winning the title this season would be a huge achievement for the club.
"Look at the spending power Manchester City have, the injuries we've had, the experience we've lost - Scholesy [Paul Scholes] for half the season, Edwin van der Sar, John O'Shea, Wes Brown.
"Then the challenge we faced in bringing in a new goalkeeper - David De Gea came in for a lot of criticism early on but he's worked hard and he's showing terrific form at a key time - and the young talent we've blooded, it would be a massive achievement," he said.
United could even win the title as early as Sunday, although that is unlikely.
However, if United win on Wednesday and City lose to West Brom and then lose to Norwich City on Saturday, United would be champions again if they beat Aston Villa on Sunday.
City will be doing all they can to delay the inevitable by beating West Brom on Wednesday although Balotelli will not be playing following his red card at Arsenal.
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