City sent shockwaves around English football in October when they thrashed United 6-1 at Old Trafford, a result that Sir Alex Ferguson described as the "worst ever day" of his career in football.
Since that memorable victory at the home of their rivals, City have kept their noses in front of United in the Premier League title race and head into Sunday's encounter having opened up a three-point lead at the top of the table.
United's preparations for Sunday's clash at Eastlands could not have been worse, with Ferguson's men reeling from back-to-back league defeats against Blackburn and Newcastle.
Nevertheless history would appear to favour United, who have not lost three consecutive games for more than a decade, when they suffered three defeats to Derby, Southampton and Tottenham when the title had already been won.
While United will also be determined to avenge their exit to City at the semi-final stage last season, City midfielder James Milner believes the derby thrashing at Old Trafford will have stung their rivals more.
"That will have hurt them badly," Milner said. "Everyone, from the players, to the management, will be more than up for it.
"As much enjoyment as we got from it, they probably felt three times as much pain. We have got to be aware of that."
Victory for City may represent something of a double-edged sword, leaving the club fighting on four fronts while United are free to concentrate on the title race and the Europa League.
Ferguson meanwhile is resigned to the fact that the club he once derided as "noisy neighbours" were now poised to regularly challenge United's position at the pinnacle of the English game.
"The way we and our supporters should look at it is that we may as well get used to it, because they are not going to go away," the United boss told Inside United magazine.
"We played them in a semi-final last year and the year before, we're both in the Europa League this year and now we are facing them in the FA Cup.
"So we have to get used to the fact that City are going to be challenging for competitions along with us.
"There's every chance we're going to meet at some point, maybe not every year, but on average it's going to be pretty regular. It's a hard FA Cup draw for us, but it will be hard for them too."
Elsewhere this weekend, romantics will be keeping an eye on events at Goodison Park, where non-league Tamworth will be hoping to pull off an upset against Premier League opponents Everton.
Former Everton captain Kevin Ratcliffe, who led the Toffees to victory in the 1984 FA Cup final, warned his old club not to take the Conference minnows lightly.
"The one thing you have to do is not give them a sniff," Ratcliffe said. "It will be tight. It's their FA Cup final. They'll love it and they'll want to make an impression."
Macclesfield, from the fourth tier of English football, will meanwhile be eyeing a shock when they entertain Premier League strugglers Bolton.
League Two high-flyers Cheltenham have received a helping hand from Arsenal as they attempt to plot the downfall of Tottenham at White Hart Lane.
Cheltenham, second in League Two, have trained at Arsenal's London Colney training centre this week ahead of Saturday's clash.
Cheltenham are expected to take 5,000 fans to London for the game against Spurs, who stand third in the Premier League.
"Cup upsets happen all the time so why can't Cheltenham Town beat Tottenham Hotspur at White Hart Lane? That could be the fairytale story of this year's competition," Cheltenham striker Darryl Duffy said.
Monday's lone FA Cup fixture sees Arsenal entertain Leeds at the Emirates, a game which may see Thierry Henry make an emotional return to action for the Gunners.
Arsenal are currently racing to complete paperwork which will allow Henry to play after the 34-year-old New York Red Bulls player agreed a two-month loan deal.