Last year, the same two teams met at the same stage in the competition, with the blue side of Manchester victorious.
However, the gulf in class now seems to be significantly smaller, and a positive result for United would highlight real progress from Ole Gunnar Solskjaer and his men.
But what should the red side of Manchester be looking out for on Wednesday evening?
Will the Reds approach the game differently to how they did in December?
With both teams entering the highly-anticipated encounter in great form, the game may well be a stark contrast to the goalless draw the same teams played out in December.
That's not to say, of course, that it won't be a cagey affair.
Less than a month ago, on the 12th of December, United and their counterparts seemed more than happy to settle for a point at Old Trafford. Perhaps this was slightly more understandable for the Reds, knowing a draw would keep them above City in the table.
The semifinal, however, is a different type of fixture; a one-way ticket to this year's final. If the game remains goalless in the latter stages, we should be expecting more goal-mouth action than we did in December's league encounter.
United may play the game in a similar fashion, knowing that last time they kept a clean sheet in doing so, but it will be interesting to see if Solskjaer's men commit more bodies forward now that they are going through a much more positive period than they were in the early, inconsistent months of United's season.
Equally, United fans would be delighted with a solid defensive performance and grabbing a goal or two in the latter stages to book their place in this year's final.
Will Solskjaer overcome his semifinal hoodoo?
Every United fan will be all too familiar with the fact that their team was beaten in three different semifinals last season – but their team seems more suited to overcoming the challenge this season.
Although the United defence still has its weaknesses, it is hard to see the team not creating chances and scoring goals at the moment, much to the delight of Solskjaer and his staff.
Hopefully, the new-found confidence within the United dressing room will transpire onto the pitch on Wednesday evening and see United play without fear in a semifinal – something they were incapable of doing last season.
Success against United's bitter rivals in the cup would give Solskjaer with a new lease of life, and would give football fans and pundits one less reason to doubt the Norweigan's ability to take United to the next level.
United would still have to be victorious in April's final at Wembley should they defeat City, but overcoming the semifinal curse would be a huge step forward.
Can United's strength-in-depth be utilised efficiently?
It is no secret that United's bench wasn't the strongest last season, leading to players being overused and Solskjaer struggling to make impact substitutions on a frequent basis.
But it is a completely different story in the Reds' dressing room this season.
United are currently blessed to have several game-changers on the bench every time they take to the field. Players like Donny van de Beek, Juan Mata, Axel Tuanzabe, and Dean Henderson have all shown great ability when they have been given a chance this season, albeit without having a huge amount of minutes to their name.
The semifinal could act as a perfect platform and provide opportunities to Solskjaer's "squad players" who have already shown they can perform on big occasions.
Perhaps if a few of these players starred against Manchester City, they would put their names in the forefront of the manager's mind and could potentially transform their seasons.
Surely, this would be a positive dilemma for Solskjaer to have.