The attackers escaped, setting a large region east of Los Angeles on edge, but about four hours later police riddled a black SUV with gunfire two miles (3 kilometers) from the late-morning carnage.
A man and woman in the SUV with assault rifles, handguns and "assault-style clothing" were killed, Police Chief Jarrod Burguan said. A third person who was spotted running away near the scene of the gun battle was detained, but Burguan said it was unclear if that person had anything to do with the crime.
It was the deadliest mass shooting in a nation all too familiar with them since 2012, when a man killed 26 children and adults at a school in the Newtown, Connecticut.
Police shed no light on a motive for Wednesday's massacre, which came just five days after a gunman opened fire at Planned Parenthood in Colorado, killing three.
"They came prepared to do what they did, as if they were on a mission," the police chief said.
Authorities also found a potential explosive device found at the social service center.
That the violence happened at a place dedicated to helping people with developmental disabilities made it even harder for some to comprehend.
"These are all disabled kids, very disabled," said Sherry Esquerra, who was searching for her daughter and son-in-law, both of whom work at the center. "She gets all the services she possibly could for these kids. So I just don't understand why somebody would come in and start shooting."
FBI agents and other law enforcement authorities converged on the center and searched room to room for the attackers, but they had apparently escaped. Cervantes, the police spokeswoman, said there were reports from witnesses of one to three gunmen.
Ten of the wounded were hospitalized in critical condition, and three were in serious condition, San Bernardino Fire Chief Tom Hannemann said. Police cautioned that the numbers of dead and wounded were early estimates that could change.
No weapons were found at the center, though authorities were investigating unidentified items in the building and brought in bomb squads, Burguan said.
As the manhunt went on, stores, office buildings and at least one school were locked down in the city of 214,000 people about 60 miles (100 kilometers) east of Los Angeles, and roads were blocked off.
Triage units were set up outside the center, and people were seen being wheeled away on stretchers. Others walked quickly from a building with their hands up. They were searched by police before being reunited with loved ones.
One witness, Glenn Willwerth, who runs a business across the street, said he heard 10 to 15 shots and then saw an SUV with blacked out windows pull "very calmly, very slowly."
President Barack Obama was briefed on the attack by his homeland security adviser.
He said it was too early to know the shooters' motives, but urged the country to take steps to reduce the frequency of mass shootings. He told CBS that stricter gun laws, including stronger background checks, would make the country safer.
"The one thing we do know is that we have a pattern now of mass shootings in this country that has no parallel anywhere else in the world, and there's some steps we could take, not to eliminate every one of these mass shootings, but to improve the odds that they don't happen as frequently," Obama said.
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