The lunchtime kick-off at Anfield is the standout tie of the weekend although this time not all the talk has been about football owing to the animosity surrounding Liverpool striker Luis Suarez's eight-match ban for racially abusing United's French left-back Patrice Evra in a Premier League game.
United supporters will travel in their thousands to the home of their arch north-west rivals and while Suarez will not be playing, tensions are expected to run high.
The same can be said of the other Saturday lunchtime kick-off at Loftus Road where Queens Park Rangers host their West London rivals Chelsea - a tie that brings QPR defender Anton Ferdinand into direct contact with John Terry for the first time since he accused the England skipper of racially abusing him.
Terry, who will appear in court next week to answer police charges of racist language towards the brother of England defender Rio, will play, according to Chelsea boss Andre Villas-Boas, and both clubs issued a statement this week attempting to smooth the waters before the derby.
Camera lenses will be trained on Terry and Ferdinand for the obligatory pre-match handshakes, while extra police and stewards have been employed for the game.
Other ties involving Premier League rivals include Everton against Fulham on Friday and Arsenal's home tie against Aston Villa on Sunday.
Meanwhile, those seeking a shock will be keeping an eye on Championship Brighton's home tie against top-flight Newcastle United and high-flying Tottenham Hotspur's short journey to Championship side Watford on Friday.
League Two Crawley Town are the lowest-ranked survivors and will travel to Hull City confident of reaching the fifth round.
The focus will be on Anfield on Saturday, though, when Liverpool face United hoping for only a fourth victory against them in the FA Cup - the most recent coming in the fifth round in 2006 when a Peter Crouch goal earned them a 1-0 win.
United gained revenge for that two seasons ago when Ryan Giggs scored the only goal in a third-round clash in which Liverpool skipper Steven Gerrard was sent off.
WEMBLEY BOUND
Liverpool, criticised by manager Kenny Dalglish for a listless league defeat by Bolton Wanderers last week, responded in fine style on Wednesday by beating Manchester City 3-2 on aggregate to reach the League Cup final, where they will play Championship side Cardiff City.
The 2-2 draw against City would have given Liverpool a huge boost as they prepare to take on United.
"We've got to Wembley. That's all we've achieved so far. We've not been there for a while, so I think that in itself is an achievement - but that's not where our ambitions stop," Dalglish said.
"We want to continue and do as well as we can between now and the end of the season. We'll enjoy the moment tonight for a wee while and then get ourselves conce
