A firefighters' spokeswoman said two people had been pulled alive from the rubble from the Morandi Bridge after a section collapsed onto an industrial area below.
The disaster occurred on a major road that connects Italy to France and other resorts on the eve of Ferragosto, a major Italian holiday. Traffic would have been heavier than usual as many people travelled to beaches or mountains.
Transport minister, Danilo Toninelli, called the collapse '˜an enormous tragedy'.
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Broadcaster Sky TG24 said the section of the bridge collapsed over an industrial zone. Firefighters have also raised concerns about gas lines.
Photos published by the ANSA news agency on its website showed a huge gulf between two sections of the bridge.
Video captured the sound of a man screaming: '˜Oh god, oh, god.' Other images showed a green truck that had stopped just yards short of the gaping hole in the bridge.
Interior minister Matteo Salvini said some 200 firefighters were responding to the accident.
He said on Twitter: '˜We are following minute by minute the situation for the bridge collapse in Genoa.'
The Morandi Bridge was inaugurated in 1967. It is 295ft high and just over three-quarters of a mile long, with the longest section between supports measuring 650ft.
The bridge is a main thoroughfare connecting the A10 highway heading towards France and the A7 highway that continues north towards Milan.
ANSA said authorities believe a structural weakness caused the collapse.