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Speaking from the scene on Cuban television, President Miguel Diaz-Canel said the blast at the historic Hotel Saratoga appeared to have been caused by a gas leak.
"In no case was it a bomb or an attack," he later told Reuters as he left the capital's Calixto Garcia hospital, where many of the injured were treated. 'It's just a very unfortunate accident."
The blast nonetheless sent a brief wave of panic through the historic old Havana neighborhood, which has gradually begun reopening to tourists after the pandemic battered the Caribbean island's crucial travel sector.
Hundreds of Cubans and tourists alike gathered near the property under a hot sun as police cordoned off the area around the hotel. Many speculated about the cause of the blast as ambulances and rescue workers carried victims from the wreckage.
State TV reported search and rescue efforts were ongoing and said it was unclear whether additional victims remained trapped in the rubble.
The government has not yet made public the nationalities of the victims, state TV said.
The hotel, housed in a more than century-old building, had been closed and only workers were inside at time of the explosion, the state-run channel added, citing Roberto Enrique Calzadilla, a representative of the military-run company that operates many of the country's hotels.
In a broadcast interview, Calzadilla said the 96-room hotel had been set to re-open in the next few days and that the workers on site were making final preparations.
He also said a gas leak appeared to be the cause.
"The workers were ... making repairs and doing all the work to open the property and in the morning they were resupplying the gas and it seems some accident caused an explosion," he said.
The blast shrouded the building and surrounding streets in plumes of black smoke.
Police and rescue workers moved quickly to cordon off some nearby government buildings, including the historic Capitolio, or capital building.
A photo from the scene showed what appeared to be at least one body with a white cloth over it. A block from the blast, a man carried a woman screaming in pain to a clinic, as onlookers begged for information about loved ones.
The neoclassical style Saratoga Hotel was remodeled by a British company after the fall of the Soviet Union and for many years was considered the place to stay by visiting government officials and celebrities.
Recently, it had lost some of its shine with the opening of new hotels in Havana, but was still a five-star venue.