Hurt by League Cup and FA Cup exits at the hands of the West London club this season, United have the chance to put a huge dent in Chelsea's hopes of finishing in the top four.
That is bad news for Chelsea, for whom the fixtures have been piling up in recent weeks courtesy of their exploits in the Europa League - a competition they are determined to avoid playing in next season.
With the title race done and dusted, Manchester City odds on to be runners-up and Reading and Queens Park Rangers already relegated, the battle for third and fourth spots has taken centre stage with Chelsea vying with Arsenal, Tottenham Hotspur and Everton for a place in the Champions League.
Chelsea are third in the final automatic Champions League spot with 65 points, one ahead of Arsenal who have one game less to play and three ahead of Spurs, who have the toughest run-in on paper as they visit Stamford Bridge on Wednesday in what could prove a decisive fixture.
Fourth is worth a Champions League play-off spot.
By the time Chelsea's interim manager Rafa Benitez locks horns again with old adversary Sir Alex Ferguson on Sunday, the pressure could have been ratcheted up a notch.
Spurs, who like Chelsea have four games to play, are the first of the contenders in action this weekend with a home match against Southampton on Saturday.
Fourth-placed Arsenal kick off a few hours later at Queens Park Rangers while sixth-placed Everton, who have doggedly refused to give up the chase for a top-four berth, must beat Merseyside rivals Liverpool at Anfield for the first time in 14 years on Sunday if they are to stay in the hunt.
Chelsea will be playing their 12th game in little more than 30 days at Old Trafford on Sunday and will be looking for a third win of the season over Ferguson's side, following a 5-4 League Cup win when Roberto Di Matteo was still in charge and a 1-0 FA Cup replay win masterminded by Benitez last month.
Benitez, who will leave Stamford Bridge later this month, has been forced to juggle his squad as a long campaign draws to a conclusion and will be asking his side to dig deep again at United, and then again against Spurs on Wednesday.
Spurs missed a trick with a 2-2 draw at lowly Wigan Athletic last weekend, but will aim to steal a march on their London rivals and move level on points with Chelsea, if only temporarily, with victory over Southampton.
Gareth Bale, who joined Tottenham from Southampton in 2007 and has since become one of the most sought-after players in Europe, believes the North London club can make up for last season's heartache when, despite finishing fourth, they were denied a Champions League chance because Chelsea won the trophy.
"We all need to stick together now and give one final push to get where we want to be," Bale said. "We have four games to go and we want to finish the job off."
EASIEST TASK
With games at QPR, at home to Wigan and away to Newcastle United left, Arsenal look to have the easiest task as they seek a 16th consecutive appearance in the Champio
