One of the key protagonists in the bad blood between the two clubs of late is Luis Suarez, after the FA decided he was guilty of racially abusing Patrice Evra, and banned him for eight games.
As the match is at Anfield, Suarez will be in his comfort zone, and it will be Evra who will be the target for the boo boys, with most of the Liverpool crowd dissatisfied that the Frenchman reported the incident fairly and accurately.
Evra has already been to Anfield once since then, when United slipped to a 2-1 FA Cup defeat courtesy of a Dirk Kuyt winner in the fourth round.
With the match on September 23, Sir Alex Ferguson's mind will already be thinking about team selection, a a big question is whether Evra will play.
It is not for reasons of concern over facing the hate mob, but more his poor form this season, which culminated in him being directly responsible for Southampton's second goal in their last match.
There is talk Evra will be dropped for this weekend's match against Wigan, with new signing Alexander Buttner coming in to take his place.
If he does, and plays well, then Evra might just find himself omitted for the Liverpool game which happens to be the following match.
It will equally be a risk for United to throw in their new signing to such a huge match at Anfield, but this is why it is wise to give him a game against Wigan to at least give him a taste of first team action.
Evra's form has been deteriorating for at least three years now. He made a key error leading to United's Champions League defeat to Bayern Munich in 2010, was responsible for Barcelona's opener in the 2011 final at Wembley via his poor positioning, and last season was an underwhelming one too.
He may be as comfortable going forward as ever, but it is defensively where he is suspect, and it is a wonder the club waited until now to give him some added competition for his place.
Evra played for France against Belarus in midweek, but was criticised for his woeful performance, and is clearly out of sorts.
There is no doubt he will be up for the Liverpool game, but he is not playing well at the moment, and the distraction of the whole occasion could make it too much of a risk to play him.
As determined as he may be to play a part against their rivals, Evra may just have played himself out of it, and with it another potential handshake drama with Luis Suarez, which might just be a good thing all round, as reigniting that particular fire is a problem either club could do without.
Would you play Evra at Anfield? Or does he deserve to be dropped?
image: © nasmac