A huge section of the Morandi Bridge collapsed over an industrial zone, sending tons of twisted steel and concrete debris onto warehouses below. Photos published by the Italian news agency ANSA showed a massive, empty gulf between two sections of the bridge.
Amalia Tedeschi, a firefighter, told RAI state TV that some 20 vehicles, including cars and trucks, were caught up as an 80-meter (260-foot) stretch of the bridge collapsed.
She said two people had been pulled alive from vehicles in the rubble. Officials said they were transported by helicopter to a hospital.
Edoardo Rixi, a transport official, told Sky TV that 22 were dead and 8 were injured in the collapse.
Video captured the sound of a man screaming: "Oh God! Oh, God!" Other images showed a green truck that had stopped just short of the gaping hole in the bridge and the tires of a tractor trailer in the rubble.
Firefighters told The Associated Press they were worried about gas lines exploding in the area from the collapse.
ANSA said authorities suspected that a structural weakness had caused the collapse, but there was no immediate explanation for what had happened.
Italy's transport minister, Danilo Toninelli, called the collapse "an enormous tragedy."
News agency ANSA said Prime Minister Giuseppe Conte will travel to Genoa later Tuesday. Interior Minister Matteo Salvini said some 200 firefighters were responding to the accident.
"We are following minute by minute the situation of the bridge collapse in Genoa," Salvini said on Twitter.
The disaster occurred on a highway that connects Italy to France, and northern cities like Milan to the beaches of Liguria.
It came on the eve of a major Italian summer holiday on Wednesday called Ferragosto, which marks the religious feast of the Assumption of Mary. The day marks the high point of the Italian summer holiday season when most cities and business are closed and Italians head to the beaches or the mountains, which means traffic was heavier than usual on the Genoa highway.
The Morandi Bridge is a main thoroughfare connecting the A10 highway that goes toward France and the A7 highway that continues north toward Milan. Inaugurated in 1967, it is 45 meters (148 feet) high, just over a kilometer (.6 miles) long.
The collapse of the bridge comes eight days after another major accident on an Italian highway, one near the northern city of Bologna.
In that case, a tanker truck carrying a highly flammable gas exploded after rear-ending a stopped truck on the road and getting hit from behind itself. The accident killed one person, injured dozens and blew apart a section of a raised eight-lane highway.