United opened a four-point gap at the top of the Premier League with a 5-0 romp at Wolverhampton Wanderers on Sunday but second-placed City will be gunning for revenge against Chelsea after losing 2-1 at Stamford Bridge in December.
Roberto Mancini's team have been unstoppable at home this season, amassing 42 goals and conceding only six to win all 14 home league games.
It will, however, be a case of the unstoppable force meeting the immovable object on Wednesday.
Chelsea have triumphed in all four matches since Italian Di Matteo took over from the sacked Andre Villas-Boas earlier this month and look to have regained the sort of form that powered them to the Premier League and FA Cup double in 2010.
Di Matteo has also managed to coax some goals out of beleaguered striker Fernando Torres, who netted for the first time since October by bagging a double in Sunday's 5-2 FA Cup quarter-final victory over second tier Leicester City.
"The important thing is we are creating more chances than before," Torres told the club's website.
"The job of a striker is to score goals and if you don't do it the people think you are playing badly but the main thing is the support of the fans and they were always with me, as were my team mates and the staff here.
"I feel the confidence of the manager now and it is a good time for me and Chelsea," added the Spaniard.
Tough-as-teak Serbian defender Branislav Ivanovic summed up the mood of the squad when he ran the length of the field to give Torres a giant bear hug after his first goal against Leicester.
"Fernando has been doing really well but he was just unlucky not to be scoring," said goalkeeper Petr Cech, standing in as captain in the absence of the injured John Terry.
"He has had a lot of assists, has been working hard for the team and it was great to see him get his reward. He must be delighted because as a striker you think of goals and on Sunday he scored twice and that is great for his confidence."
With fifth-placed Chelsea still involved in three competitions and the games coming thick and fast towards the latter stage of the season, Di Matteo is likely to continue his rotation policy and drop Torres back to the bench against City.
Didier Drogba, rested against Leicester after playing for 120 minutes in the midweek Champions League victory over Napoli, is expected to lead the attack.
Terry, Frank Lampard, David Luiz, Ashley Cole, Michael Essien and Brazilian Ramires are also set to return to the starting line-up.
Controversial Argentina striker Carlos Tevez could feature for City for the first time since September.
The return of Tevez, whose fall-out with the club ended in disciplinary action for an unauthorised three-month absence earlier this season, could lift Mancini's men after they were knocked out of the Europa League by Sporting on Thursday.
In other Premier League matches, strugglers Blackburn Rovers entertain Sunderland on Tuesday while one day later
