Rocco Forte's five-star, 165-bedroom Lowry hotel in Manchester is up for sale for more than £40m.
The luxury hotel group, which owns and operates 11 hotels in Europe, hopes to retain a management contract to run the hotel under new owners.
Located opposite Trinity Bridge, the hotel is being marketed by Christie + Co and is believed to have already attracted considerable interest.
The off-loading of the property is part of the company's strategy to only retain ownership of hotels in major international cities. The finance achieved by the sale will allow the group to look at expansion in capital cities across the globe.
Richard Power, group communications director of Rocco Forte Hotels, said the Lowry has a higher share of domestic business than the other hotels in the group.
"Around 98% of its business comes from within the UK," he explained. "All our other hotels have a broader international spread."
The Lowry is one of three properties currently owned and operated by Rocco Forte Hotels in the UK, alongside Brown's hotel in London and the Balmoral in Edinburgh, both which will remain company-owned.
The company also has hotels in Brussels, Frankfurt, Berlin, Munich, Rome, Florence and Sicily.