Defeat for Chelsea, 11 points behind United in the Premier League title race with eight games to play, would put manager Carlo Ancelotti under huge pressure less than a year after he led the team to a league and FA Cup double.
The Italian knows his future is on a knife-edge after an uneven season and recent history between the two clubs suggests that the Champions League tie, which concludes at Old Trafford next Tuesday, will be decided by the slimmest of margins.
Only two of their last 11 competitive matches have been settled by more than one goal, while their most famous meeting, the Champions League final in Moscow, went to penalties.
Chelsea go into the match with a good record at home against United. They are unbeaten in their last 10 matches against Sir Alex Ferguson's men, including last month's Premier League game when they came from behind to win 2-1 with a goal from David Luiz and a Frank Lampard penalty.
Chelsea's front men, however, have been lacklustre with Didier Drogba, Nicolas Anelka, Salomon Kalou and Fernando Torres scoring just three goals in their last nine matches.
NO GOALS
Torres, two months after his £50 million move from Liverpool, is still looking for his first goal for Chelsea after eight appearances, and might start on the bench.
Chelsea drew 1-1 at Stoke City on Saturday, though they played better than the result suggested, and Ancelotti is looking forward to Wednesday's game.
"The condition of the players is good psychologically and physically. We don't have any problems and we are ready to play United. We have the confidence to do our best and win," he said.
"We know that United have the same opinion. It will be a very exciting game, a very tough game. We know everything about Manchester United and they know everything about us. Whoever deserves to win, will win."
United recovered from trailing 2-0 to win 4-2 at West Ham United where Wayne Rooney scored a hat-trick and Javier Hernandez the other goal.
Rooney blotted his performance by a foul-mouthed rant live on television, for which he has been charged by the FA, but he will play on Wednesday and look to repeat the goal he scored in the league match at Chelsea last month.
Saturday's victory at West Ham left United seven points clear of Arsenal at the top of the table.
Defender Chris Smalling, whose trip on Yuri Zhirkov led to the penalty that cost United the league game at Stamford Bridge, said the mood in Manchester was confident.
"Those things happen in your career and it's important how you react, and we've kicked on with our performances. We're now going into Wednesday's game with a lot of confidence - and so we should."
Teams (possible):
Chelsea: 1-Petr Cech; 3-Ashley Cole, 26-John Terry, 33-Alex, 17-Jose Bosingwa; 7-Ramires, 8-Frank Lampard, 5-Michael Essien, 15-Florent Malouda; 11-Didier Drogba, 39-Nicolas Anelka
