Sir Alex Ferguson could be forced to do without more than half of his first-choice line-up for what has become a pivotal Premier League fixture with Aston Villa this weekend.
Back-to-back defeats by Liverpool and Fulham mean that United could have slipped to second place by the time they kick off against Martin O'Neill's side on Sunday.
For that to happen, Liverpool have to beat Fulham at Craven Cottage on Saturday evening and United start the weekend with the advantage of a game in hand over their biggest rivals as well as a single point lead.
But it is clear that the champions' nerve is set to be tested far more robustly than anyone would have imagined a couple of weeks ago and Ferguson's preparations for the arrival of Villa have been anything but ideal.
Recent red cards for Nemanja Vidic, Paul Scholes and Wayne Rooney mean all three are suspended while Vidic's centreback partner, Rio Ferdinand, faces a battle to recover from a groin strain that caused him to depart early from England's midweek win over Ukraine.
In addition, Dimitar Berbatov is struggling with an ankle injury, midfielder Anderson suffered a knee injury on World Cup duty with Brazil and Carlos Tevez will be coping with a cocktail of jet lag and shock after featuring in Argentina's 6-1 thrashing in Bolivia on Wednesday.
Like United, Villa have lost momentum of late, taking just one point from their last five matches to concede their place in the top four to Arsenal.
Villa striker Gabriel Agbonlahor had not been born the last time Villa won at Old Trafford, but he sees no reason why that cannot change this weekend.
"Our away form has been good overall this season," he said. "Too many teams go to Old Trafford and just give up without even trying. But teams like Everton, who went there with a positive attitude, almost got something."
Alan Shearer's attempt to save Newcastle from the drop kicks off when Chelsea visit St James' Park on Saturday.
Given that the west London club still harbours hopes of getting back into the title race, Shearer could scarcely have had a more testing start to his managerial career.
But the former England striker is confident that he can inject sufficient spirit into the Magpies to ensure they secure the points needed to stave off relegation and its financially calamitous consequences.
"We have a massive fight on our hands in difficult circumstances but we will give it a right good go," Shearer vowed.
Cesc Fabregas is expected to be involved against Manchester City in what will be the Arsenal captain's first appearance since he suffered a serious knee injury against Liverpool on December 21.
Arsenal will also have Theo Walcott and Emmanuel Adebayor back from injury as they seek to extend their 16-match unbeaten run in the league.
Manager Arsene Wenger is delighted to have Fabregas back in action with a Champions League quarter-final date with Villarreal and an FA Cup semi-final against Chelsea coming up this month, but he recognises the Spanish midfielder will need time to bed back into the side.
"Cesc is ready to play again, but he'll need two or three games to be back at his best," Wenger said.
"But it will be good to have him in the team. We've got eight games in 25 days, all of them critical."
West Brom boss Tony Mowbray has acknowledged that his side, currently propping up the league, must beat Stoke at home on Saturday if they are to have any realistic prospect of avoiding relegation and Middlesbrough, who are away to Bolton, find themselves in a very similar position.