The company is ending its weekly night at the Nation on Wolstenholme Square. It is believed that falling numbers and a boom in other clubs and bars are behind the decision.
The move, which comes on the eve of the club's 10th birthday, marks the end of an era.
Cream was founded in Liverpool and grew to be one of the most famous club names on the world. It has always been identified with the city.
The club plans to continue to hold special events across the UK under the Cream brand such as Cream arena tours and the Creamfields festival.
But the regular weekly Saturday nights will cease and the head office of the operation will move to its London base.
The nightclub in which Cream takes place - Nation - will not close and other events which take place there are set to continue. That includes the Lomax live music venue and club nights such as Medication and Bugged Out.
Cream director James Barton said: "It is something which is unfortunate but I think we have to make these sorts of decisions. At the end of the day we are businessmen."
Superclubs such as Cream have been struggling across the country. Other big nights, such as Gatecrasher in Sheffield and Ministry of Sound in London, have also been struggling to attract the bumper crowds that they could once command.
One of the reasons is the proliferation of bars with late licences who do not charge to get in, and provide DJs and dance floors.
Cream, originally launched by James Barton and Darren Hughes, started as a one-off night and soon became one of the coolest club nights in Britain, developing into a business empire that included record releases, international tours and merchandising.
The Cream decision also comes in the wake of a devastating fire which destroyed Garlands, another of Liverpool's trendiest nightspots.
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