Lancashire Fire and Rescue say that eight fire engines and two aerial ladder platforms at the former St Joseph’s Orphanage on Mount Street, Preston.
Firefighters were called to the incident at approximately at 19:48.
They are working to extinguish the fire and make the building safe.
Fishergate is closed to vehicles between the junctions of Chapel Street and the Fishergate Centre. Firefighters expect to be at the scene for most of the evening. No injuries have been reported.