Badly beaten 4-1 by their local rivals in September, United have home advantage this time and go into the game buoyed by successive victories over Olympiakos, to reach the Champions League quarter-final, and West Ham.
Saturday's 2-0 win at Upton Park, where acting captain Wayne Rooney scored one of the goals of the season from more than 50 metres, helped ease the pressure from manager David Moyes, who has struggled in his first season after taking over from Alex Ferguson.
"You get three points for winning any game but there is an added importance of winning the big games," Moyes told reporters.
"It's not been something we have done well enough this season, so it would be nice if we could get it in this game.
"Their ability to score goals would be in anybody's mind because if you look at the record this year they have been terrific."
City trail Chelsea by six points but have three games in hand and with a superior goal difference would go top by winning two of them. They will again be without their leading scorer, Argentinian striker Sergio Aguero, who has a hamstring injury but captain Vincent Kompany is available after suspension.
City have been solid in defence, not conceding in the last three league games, but despite scoring five times without reply against bottom-of-the-table Fulham on Saturday, their total of 76 goals is now six fewer than rampant Liverpool.
Brendan Rodgers's side have joined the title chase with six successive victories, scoring 24 goals in the process. Having won 6-3 at Cardiff at the weekend, they will be expected to defeat another of the relegation-threatened sides, Sunderland, at Anfield on Wednesday.
The combination of Uruguay's Luis Suarez and England's Daniel Sturridge continues to demolish opposing defences. Suarez's third hat-trick of the season on Saturday took him to 28 goals for the season, despite missing the first five matches because of suspension.
Sturridge has provided many of the assists as well as scoring 19 times himself.
For Sunderland, it is one of two games in hand on the teams immediately above them. Swansea City, four points in front of Gus Poyet's side, have dropped into the bottom six and will fear a backlash on Tuesday in their game at Arsenal.
The London side suffered a humiliating 6-0 defeat by Chelsea on Saturday in Arsene Wenger's 1,000th match in charge.
The same night Newcastle play Everton, who are challenging for a Europa League place, and in the other midweek match West Ham host Hull City on Wednesday with neither side certain of retaining their Premier League status.
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- Manchester United
- Manchester City
- David Moyes
- Wayne Rooney