It has been almost eight years since this particular pair clashed at Old Trafford, but if this season’s earlier encounter at St. Mary’s is anything to go by, we could be set for some fireworks.
On that occasion, it was Robin van Persie who proved to be the key in the Saints’ eventual undoing, but one can bet that individual struggles will be taking place pitch-wide for the whole of the 90 minutes.
Here are the five most important matchups to watch for during this Wednesday's game.
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Giants amongst men inside their own parameters, both Nemanja Vidic and Rickie Lambert have enjoyed some great form for parts of the current campaign in defence and attack, respectively.
Sir Alex Ferguson has been able to call upon a fully fit Vidic/Rio Ferdinand combination for decent stretches of the campaign, and if there is any aspect of the game where the latter thrives more than any other, it is in the air.
As the sole striker, it’s likely to be Lambert’s job to bring down any aerial ball he can, holding up possession for those around him and providing an all-round target man for his midfield to aim at.
With 10 league goals to his name already this season, it’s clear that the 30-year-old is keen to use his considerable experience against even the biggest sides, especially considering he’s already scored against the Red Devils this term.
Southampton’s striking star is a threat in the air, as well as from long and short range, and it’s more than likely that Vidic will have his work cut out for him as his side currently boast the eighth worst home defence in the division.
With Shinji Kagawa and Tom Cleverley both adopting more creative positions in recent months, it has been the duty of Michael Carrick at times to ensure that United’s defence isn’t altogether exposed by the opposition midfield.
In opposite fashion, Gaston Ramirez is arguably Southampton’s premier playmaker on his day and is likely to take up position not far behind the rampaging Rickie Lambert.
Should this be the case, it is safe to assume that Carrick will be looked at as the Uruguayan’s caretaker for the evening, ensuring the Saints' catalyst can’t show the great potential he did last season in Serie A.
Admittedly, Ramirez has found it difficult to settle into England’s pace at times. Of his 16 appearances this term, only six have been for the whole 90 minutes.
Carrick will indeed still find the freedom to help out in attack, setting the pace of the break as he has done so often in recent months, but containing Ramirez’ creative juices should be a priority for the 31-year-old.
A battle of the starlets, if you will, both Rafael da Silva and Luke Shaw are looked upon by their clubs as future stalwarts at full-back, despite there being a five-year age gap between the two.
As is the trend amongst most modern wing-backs, both youngsters have significant attacking intent to their play, rather than the "defensive" role their position would have you believe.
On Wednesday evening, the prospective back-and-forth between these two will make for lip-smacking football, with both players as eager as any to obtain recognition at the club they play for.
A lot of this matchup’s result could rest on just who gets the better of the wide positions, With both Rafael and Shaw not afraid of getting forward whenever possible, it could come down to just who can get behind who on a more regular basis.
The attack-minded full-back would appear to be a sacrifice many a manager are willing to put up with these days, and Rafael’s battle with Shaw may just show what the future holds for Brazil and England’s hopes in that spot, respectively.
Throw in as many defenders as you can, make your tactics as strategically tight as possible. Yet there are just some things that even the most rigid of sides can’t overcome.
Robin van Persie has the potential to be that on any given day.
Which is why, for the majority of the Southampton encounter, a large portion of the Saints’ hopes of surviving may rest on whether or not the man between the sticks is having a good day at the races.
This time around, that man is likely to be summer signing, Artur Boruc, who has had far from a magnificent spell since moving to St. Mary’s.
That being said, the former Celtic star has kept two clean sheets in his last two matches, making for a potentially close battle when the Pole makes his way to Old Trafford.
With six goals and two assists in his last five fixtures, it is fair to say that the Dutch sensation is enjoying a magnificent run of form.
While a great share of responsibility may lie with his defence, Boruc will be tested by the Red Devils’ main man, and he will need to be equal to the test.
Despite getting off to a rocky start in his Southampton career, summer signing Maya Yoshida has gradually slotted into the Saints’ defence with encouraging ease of late and is arguably now the club’s best centre-back with Jose Fonte out injured.
Although the Japanese defender has certainly helped his side’s clean sheet record, he still hasn’t been able to influence matters much away from home, seeing Mauricio Pochettino’s side account for the worst away defence in the league.
On average, the Saints have conceded 2.36 goals per game when playing in unfamiliar territory, and the presence of Wayne Rooney may not make the south coast club’s hopes of improving that ratio much brighter.
With Van Persie playing the role of target man, Rooney has, at times, slotted into a more subdued, playmaking role and is encouraged to make things easier for his Dutch striking partner.
Although the English forward is likely to float around with great freedom, a lot of Rooney’s forays forward will come from central positions. Yoshida will need to lead his defence well if they are to shut the 27-year-old out on Wednesday.
With 10 goals and 11 assists to his name already this season, “Wazza” will be hopeful of adding to his tally against the division’s worst away defence and will likely butt heads with Yoshida.