The flagship Virgin Megastore, situated in New York's Time Square, is to close in April.
The 75,000 sq ft record store has faced an uncertain future since the entertainment arm of the company was sold in August 2007.
According to Billboard, the Times Square store is closing because owners Related and Vornado want to lease the property more profitably to a new tenant.
The record store, which is the biggest in New York, is one of six Virgin Megastores still in operation in America.
Despite falling record sales, the store has remained profitable, with an annual profit of $6million.
In the UK, Virgin Megastores were rebranded Zavvi following a management buyout in September 2007. The company has since gone into administration.
The Virgin Megastore in New York's Union Square is unaffected by the closure.
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