City inflicted a humiliating 6-1 defeat on United when the the clubs met in the league at Old Trafford in October, a result Sir Alex Ferguson later described as his "worst ever" day.
United go into Sunday's collision at Eastlands on the back of consecutive defeats that have allowed City to open up a three-point lead at the top of the table heading into the second half of the season.
While an early FA Cup exit for United on Sunday could give holders City a valuable psychological edge over their great rivals, Mancini has warned his men to expect a ferocious response from Ferguson's team.
"Derbies are always difficult and maybe this one will be even harder because United are angry after these two defeats and because we beat them at Old Trafford earlier in the season," Mancini said.
"There are a lot of issues in this game. Two defeats in a row does not happen to them very often. But one thing is certain -- they have a strong mentality and always react positively after a defeat.
"Remember, after losing to us in the league they strung together seven wins and a draw. They have some injuries at the moment but they are still a strong team with good players. That is why they are always dangerous."
United, without an FA Cup win since 2004, have plenty to think about but Ferguson maintains he will not be discussing the 6-1 loss with his players.
"I won't be mentioning that," Ferguson said.
"I always say that in the FA Cup I would take anyone in a home draw and so the advantage is with City in that respect but it's a cup tie, a local derby and anything can happen in these games.
"It's amazing that (not having won since 2004). It's not a motivating force but it may be for the players that haven't got medals, particularly Rio Ferdinand.
"Rio mentioned that to me last year, that he doesn't have an FA Cup medal and I couldn't believe that, because of the amount of time he's been with the club."
After seeing his team lose ground in the title race with consecutive defeats by Blackburn Rovers and Newcastle United, Ferguson is confident of a response from United.
He also feels that the champions' experience will prove crucial in the final weeks of the season.
He added: "At the moment that's obvious because we've won the title so many times. I think from the players on the field, Tottenham are not short on experienced players and neither are City.
"That may help them and it could help them but if questions are being asked about us at the moment, it's only because we've had two bad results.
"Only a couple of weeks ago everyone was talking about how our experience was going to be important in the run-in and I think it will be."
United still have a lengthy injury list, with defender Chris Smalling set to return to training on Monday following tonsillitis.
Jonny Evans, Nemanja Vidic, Darren Fletcher, Tom Cleverley, Ashley Young, Michael Owen and Fabio da Silva are all on the sidelines with injury.
City have their own problems, however, with Gareth Barry suspended, Yaya Toure and Kolo Toure heading off to the Africa Cup of Nations and Mario Balotelli, Edin Dzeko and Samir Nasri struggling for fitness.
Even though City are desperate to secure a first league title since 1968, Mancini is determined to match last season's achievement of lifting the FA Cup.
He said: "It's the FA Cup and it's important for us. We won last year and want to get to the final if possible.