The Mid City House plot at the bottom of Pinstone Street has planning permission for 298 apartments and shops.
Retailers including the British Heart Foundation and Amplifon have moved out.
But now, the four-storey concrete-clad office building is being sold. An asking price has not been disclosed.
The site is owned by property developer Richard Edlmann. A reason for the sale was not given.
Mid City House is opposite major development as part of the city council’s Heart of the City 2 scheme, which includes plans for hundreds of flats.
But a spokesman for estate agents Savills said there was huge demand for apartments in Sheffield and it would not harm the authority’s scheme.
He also said the planning permission was due to expire ‘fairly soon’.