Television footage showed the building's facade ablaze on Thursday night, with burning segments falling to the pavement and small explosions audible inside. Witnesses said the fire, fanned by strong winds, spread to the entire building in about half an hour.
Residents could be seen calling for help from balconies. A fireman had to jump from the first floor to a crash mat below. Other footage showed two people stepping from a balcony onto a crane before being lowered to street level.
Prime Minister Pedro Sanchez was on his way to the scene after expressing support for those affected and praising firefighters.
The fire began on Thursday evening on the fourth floor of the building in an affluent neighbourhood of Spain's third-largest city and spread to other apartments, emergency services said on X.
Valencia's mayor, Maria Jose Catala, told reporters that firefighters had not yet entered the building but were able to confirm four people had died. Fifteen people were injured, six of them firefighters, but their lives were not at risk.
Firefighters were inspecting the building with cranes and drones to assess the risk of its collapse before entering, Catala said in an interview on state broadcaster TVE.
The building, comprised of two towers linked by what its developers described as a "panoramic lift" had 138 apartments, newspaper El Pais reported.
Pilar Bernabe, the government's representative in Valencia, said it was hard to say how many people were missing because it was "a building with many flats, flats in which there were people of foreign nationality, whose location is more difficult to pinpoint".
Esther Punchades of insurance inspection agency APCAS told TVE a lack of firewalls and the use of the plastic material polyurethane on the facade would have contributed to the rapid spread of the blaze.
A 2007 promotional video by the building's developer highlighted the "innovative material" used to clad the building's exterior, which passed "rigorous quality checks".
The spread of a fatal fire in the Grenfell Tower block in London in 2017, Â that killed an estimated 80 people, was blamed on the use of highly flammable external cladding.
Strong winds also played their part. A policeman told Reuters that the wind was so strong at times that it was pushing back the water being hosed by firefighters.
The city has decreed three days of mourning and suspended the start of a month-long annual festival.
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