In what is arguably West Ham's biggest game since their defeat in the epic 2006 final against Liverpool, Slaven Bilic will be looking to mastermind another famous result and secure a place in the semi-finals at Wembley.
The East Londoners have won their last four games on the bounce while the Red Devils have lost back-to-back games against West Bromwich Albion and arch rivals Liverpool in the Europa League on Thursday night.
But Bilic is facing something of a defensive headache with James Collins, Sam Byram and James Tomkins all out with the game also expected to come too soon for key man Winston Reid.
That means Michail Antonio may have to continue to deputise at right back although Joey O'Brien should make the squad.
The big question is will Bilic be prepared to risk young Reece Oxford again after his error allowed Everton a one-goal lead at Goodison Park last time out.
Oxford, 17, was withdrawn at half-time in that game and it remains to be seen whether Bilic risks the green but supremely talented defender at Old Trafford.
His other option is to move the superb Cheikhou Kouyate into central defence alongside Angelo Ogbonna but like Antonio it takes away from West Ham's presence and threat in those players' normal areas of the pitch.
Should Bilic gamble on Reid he can do so safe in the knowledge that he has Kouyate as a fall-back option if so needed.
Make way Emenike?
Elsewhere the Hammers boss must give a start to deadly striker Diafra Sakho in place of Emmanuel Emenike.
Sakho returned last week after three months out through injury and came on to devastating effect with a goal and an assist against Everton.
Emenike has worked hard in the Hammers' last three games harrying defences and running the channels without offering too much of a goal threat.
His work has been very unselfish but Sakho offers all that and more and will be fresh and hungry to make up for lost time.
The other option for Bilic is to bring Joey O'Brien in to free up Antonio to move back into midfield or keep the powerful star at right-back and leave himself with three midfield options for the right hand side with Lanzini likely to start and Victor Moses back on the bench.