Fire crews were still at the former St Joseph's Orphanage this morning after working through the night to bring the blaze in the upper floors and roof under control.
The building, which has been derelict for years, was said to be too dangerous for fire investigators to enter.
And although it is not thought anyone was in the property, emergency services say they cannot be sure until a thorough search has been carried out.
"We will probably send the search dog in to check it," said a fire brigade spokesman.
"At the moment we can't make entry into the building because it is very unsafe. There has been significant damage to the floors.
"Without going in we don't know for sure if there was anyone in it."
An investigation is being carried out into how the fire started. The alarm was raised around 7:45pm.
The first fire crews on the scene called for more back-up. Eventually there were 10 fire appliances at the incident.
They included two aerial ladder platforms (ALPs) used to fight the blaze from on high.
Just before midnight some crews were stood down, leaving three fire engines and the two ALPs to continue damping down throughout the night.
Three roads - Fishergate, Mount Street and Theatre Street - were closed to traffic during the incident and diversions remained in place this morning.
Fire brigade group manager Tom Cookson, who led the operation, said during the night: "The building is not of sound structural integrity, therefore firefighters are not entering the building.
"All out operations are being completed externally. The main firefighting is by ALPs and ground monitor checks from the courtyard area."
Asked about the possible causes of the blaze the fire brigade spokesman said: "We don't know at this stage. We can't speculate."
Parts of the former orphanage, which is attached to the old Mount Street Hospital, are in the process of being dismantled to make way for luxury apartments.
Demolition work is scheduled to begin on Monday, with the building which was badly damaged already earmarked to be the first to come down.
The historic site has been a frequent target for vandals and a place used regularly by rough sleepers.