The atmosphere at Old Trafford will be electric with United looking to overturn a 2-1 deficit in the Carling Cup semi-final second leg.
But with Manchester guaranteed some games should England be awarded the 2018 World Cup, Greater Manchester Police assistant chief constable Ian Hopkins hopes the fans will be on their best behaviour.
Rowdy: Police in riot gear control fans after the Carling Cup semi-final first leg
He said: 'As one of the host cities for the 2018 World Cup bid, the second leg truly is a great day for Manchester to shine.
'We would ask that fans play their part by behaving sensibly and do the city proud.
'Yes there is going to be banter between the fans, but it is when that banter turns into aggressive and violent behaviour that the city of Manchester will suffer.
'I would like to stress that although the rivalry has always been there between the fans, previous derby matches have passed off largely peacefully and without major incident.
'I would ask that fans adhere to this tradition on Wednesday, regardless of what happened in the first leg.
'We will not hesitate to make arrests of troublemakers. Greater Manchester Police is very experienced at policing football matches and this game will be no exception.'
Trouble: Manchester United fans let off a flair before the Carling Cup semi-final
Both City's goals in the first leg came from Carlos Tevez, who was involved in a touchline spat with his former United team-mate Gary Neville.
That incident has prompted concerns there could be trouble in the return match. However Hopkins insists the police are well equipped to cope.
He added: 'Overall the vast majority of people were as we expected at the first leg - well behaved and enjoyed a lively and entertaining football match.
'We had instances of disorder between rival fans during the match. My officers dealt with some challenging and potentially dangerous situations very effectively.
'The derby is always highly anticipated by both sets of fans and our aim is to help make the occasion a safe and enjoyable one.
'This particular game is not only a Manchester derby, but the semi-final of the Carling Cup, meaning that no matter what, there will be a representative of Manchester at Wembley for the final.'
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