The board held a closed-door meeting on whether to join the government's lawsuit against the state over the law, which bars police in many cases from turning over suspects to federal immigration agents for deportation.
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The board voted 4-0 to pass a resolution that blasts the state's sanctuary law.
"We must be certain that we are not providing assistance to undocumented immigrants who have chosen not to follow the rules. We need to look at every tool available to ensure public safety in the general public and homeless population," said Supervisor Lisa Bartlett.
The supervisors also said they're going to legally challenge the state's law in court.
Earlier, activists called on supervisors to abstain from fighting the sanctuary law while playing music and holding signs to protest the decision. Along with the immigrant advocates were supporters of President Trump.
The backlash comes a week after the sanctuary law was also challenged by the small city of Los Alamitos, when the council voted to opt out of the policy.
The county moved this week to improve communication with federal immigration agents by publishing the release dates of inmates online. The sheriff's department used to screen inmates in the county's jails to help Immigration and Customs Enforcement agents identify those subject to deportation but had to stop when the state law passed.
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Orange County, which is home to Disneyland and wealthy beach communities where many people vacation, has a five-member board of supervisors, and all are Republican.
The Associated Press contributed to this report.