United, bidding to repeat the club's 1999 Treble, are defending a three-point lead over Chelsea, who host Bolton Wanderers in the day's other early kickoff.
But just as the season reaches its decisive final weeks, with the two top clubs having four games left to play, United are running out of defenders.
Five missed their midweek win over AC Milan -- Gary Neville, Rio Ferdinand, Nemanja Vidic, Mikael Silvestre and midfielder-turned-defender Kieran Richardson -- though Neville could yet be fit on Saturday.
A fear that will haunt Ferguson throughout the game on Merseyside is that further injuries at the back could spell calamity ahead of Wednesday's Champions League semi-final second leg with Milan at San Siro.
Ferguson has little in the way of reserves to draw on, as even Youth Cup centre-half Craig Cathcart has suffered a long-term injury after being drafted into the first-team squad.
It all sets things up nicely for Everton, who are fifth in the table and have almost certainly earned themselves a UEFA Cup slot for next season.
The Toffees, with Andy Johnson up front if he recovers from a sprained ankle in time, will also want to make amends for a 3-0 defeat at Old Trafford in late November.
More poignantly, their fans will be remembering former Evertonian and England 1966 World Cup winner Alan Ball, who died of a suspected heart attack at his home on Tuesday night, aged 61.
EUROPEAN DISTRACTIONS
Chelsea, who host United in a potential title decider on May 9 and meet them again 10
The Blues face Bolton after a 1-0 home win over Liverpool in the first leg of their Champions League semi-final at Stamford Bridge.
Chelsea have had to dig deep in the closing stages of the season but have been lifted by the return from injury of Joe Cole and the scoring consistency of Didier Drogba.
Bolton, level on points with Everton and similarly on course for the UEFA Cup, are notoriously difficult to break down, though, and could well do neighbours Manchester United a favour by taking a point off the champions.
Liverpool, third in the table and assured of a place in the Champions League qualifiers, will probably just want to avoid injury ahead of next Tuesday's second leg with Chelsea in their game at Portsmouth.
Arsenal need only a point from their remaining three games to join Liverpool in those qualifiers and get their first chance at home to Fulham in Sunday's London derby.
Fulham are one of five clubs battling to avoid filling the two slots left to accompany Watford on their way down into the second division next season.
Two of those candidates meet on Saturday, with West Ham United, second from bottom, able to go level on 35 points with Wigan Athletic, currently 16th, if they can beat Paul Jewell's men at the JJB Stadium.
Sheffield United, 17th, can steer clear of the drop zone by defeating already relegated Watford, but victory is a much taller order for Charlton Athletic, who are third from bottom and face Blackburn Rovers at Ewood Park.
