The form of both sides could hardly be more of an opposite at present, with the Red Devils enjoying excellent form and ruthless efficiency, while Harry Redknapp's side are languishing at the foot of the table.
The last time these two teams met, United won 3-1 thanks to goals from Jonny Evans, Darren Fletcher and Javier Hernandez.
Here are the five key battles that should decide round two.
Following his match-winning display in the FA Cup fifth round against Reading, Sir Alex Ferguson is likely to reward Nani with a start against QPR.
The Portuguese winger has been in patchy form all season, but if he were to regain it at this stage of the campaign, it would only mean good things for the Red Devils.
If he is played on his favoured right side on Saturday, expect erratic full-back Armand Traore to be charged with stopping him.
The QPR man will be well aware that should he give his opponent an inch, a mile could be taken.
Both Robin van Persie and Wayne Rooney were given some well-earned rest during the FA Cup clash with Reading.
But with a crucial spell of games on the horizon, Sir Alex is likely to recall both to the starting XI for Saturday's Premier League game at Loftus Road.
Wayne Rooney should operate in his now familiar surroundings of attacking midfield, where he'll come up against the brutish Cameroonian Stephane Mbia.
Theirs is likely to be a very physical battle, as Mbia strives to stifle the Englishman's creativity and attacking influence.
It seems almost laughable, but Adel Taarabt claimed earlier this season that "I have been told that the president of Anzhi and people from Barcelona have asked about me" (via The Mirror).
The Moroccan's form for QPR this season has been decent at times, but certainly not worthy enough for him to one day play alongside Lionel Messi and co. at the Camp Nou.
He gave United a small share of trouble when the two teams met last year, but he is not currently playing at a level to truly worry Sir Alex's side.
The ever-improving Rafael will be required to track Taarabt when he takes off down the left flank, restricting the attacking midfielder's time and space with the ball.
It is no coincidence that Nemanja Vidic's return to fitness has seen the Red Devils' defensive record markedly improve.
United have conceded only five goals in their last eight games, while an opposing team hasn't scored two in a game against them since January 6.
Monday night he was superb, throwing himself into challenges, both aerially and on the ground, with typically unbridled passion and abandon.
Bobby Zamora is likely to earn a start in attack for QPR in the place of Jamie Mackie and will need to be at his very best to get the better of his Serbian opponent.
The sheer amount of money QPR paid to land the services of Christopher Samba this past January boggles the mind.
No club of a similar size should ever be in the position to pay a £12 million fee and wages totalling £100,000-a-week, let alone one currently in severe danger of relegation (via The Guardian).
That's not to say that Samba isn't an excellent player and a rock-solid defender—he is. Robin van Persie will likely have a tough time trying to maneuver his way past the Congo international on Saturday.
This battle, like the game on a whole, may very well come down to a matter of quality.
Who do you think Sir Alex will play vs. QPR?