In what promises to be one of the most intriguing games of the season so far, Avram Grant's resurgent Hammers will be looking to overturn top-of-the-table United to further enhance their chances of avoiding the drop. The Red Devils, however, will have other ideas as they bid to increase their lead over closest rivals Arsenal and take one step closer to regaining the title they lost to Chelsea last year.
With both sides desperate for three valuable points for very different reasons, expect the weekend's best viewing to be found in east London. Here are five key battles which could determine whether the points stay down south or head back up to Old Trafford.
Scott Parker v Michael Carrick
West Ham's player of the year for the last two seasons, Parker has continued his impressive form into this campaign, despite his side's lowly league position. His performances have gained recognition from England boss Fabio Capello, who handed him only his second competitive start against Wales last weekend. The ex-Chelsea man put in another eye-catching display for his country and is sure to play a key part for the Hammers against Manchester United.
Sir Alex Ferguson will likely opt to give Michael Carrick a start on Saturday, with Paul Scholes suspended after picking up his 10th booking of the season against Arsenal in the FA Cup. The cultured midfielder will be looking to impress against his former club but his lack of mobility could see him struggle to cope with the energetic style of Parker and boyhood Irons fan Mark Noble.
Verdict: Scott Parker
Matthew Upson v Wayne Rooney
West Ham skipper Upson has rediscovered his best form over the last few games, no surprise given his side's recent upturn in fortunes. The defender, who is out of contract this summer, should be dominant in the air against Wayne Rooney and likely striker partner Javier Hernandez, but could struggle when the ball's on the ground.
Rooney is finally showing signs of his old self and his pace and movement could be too much for Upson and the unpredictable Manuel Da Costa to handle. The United forward should also be fresh for Saturday's clash after being released from the England squad for Tuesday night's friendly with Ghana.
Verdict: Wayne Rooney
Rob Green v Edwin van der Sar
After his costly error at last summer's World Cup and some unconvincing displays for West Ham at the start of the season, Rob Green looks to be back to his best as he bids to help his side stay in the top-flight.The former Norwich stopper turned in a man-of-the-match display against Tottenham just over a week ago and he could very well be just as busy against Rooney and Hernandez on Saturday.
Van der Sar has been in similarly good form of late, most memorably in the 2-0 FA Cup win at home to Arsenal.The likes of Demba Ba, Carlton Cole and Frederic Piquionne will pose a major aerial threat in the Dutchman's area and he's likely to need some help from Vidic and Smalling to help deal with West Ham's attacking trio.