The Northern Ireland Fire and Rescue Service (NIFRS) is currently in attendance at the scene.
Shoppers and staff were evacuated from the five-story historic building at around 11am on Tuesday.
Huge plumes of black smoke and flames could be seen coming from the roof of the Bank Buildings, which is home to the Primark store.
The store has recently undergone refurbishment.
Social media posts show the smoke billowing from right across Belfast.
In a statement, a spokeswoman for the NIFRS said: “NIFRS received a call at 11am today to a fire on the top floor of the Primark building - a five-storey commercial property in the Castle Street area of Belfast.
“11 appliances are in attendance. The building has been evacuated.
“The public are advised to avoid the Castle Street/Royal Avenue area whilst the incident is ongoing.”
The Police Service of Northern Ireland also issued a warning to motorists to avoid the area.
A number of diversions are in place at Bridge Street, High Street, Castle Street and Queen’s Street as well as Royal Avenue and North Street to allow the fire service to deal with the ongoing incident.
Police have advised drivers to seek an alternative route.