He said secession was not the answer to California's policies that clash with President Donald Trump's administration.
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The mayor maintained the federal government cannot withhold funding if Los Angeles refuses to cooperate with immigration policy "with a gun to the head."
Garcetti said it violates the 10th Amendment.
He again stated Los Angeles was not a sanctuary city, explaining police would turn over arrested felons to federal authorities who have a warrant.
He discussed the positive economic impact of immigrants, citing a new study finding foreign-born residents contributed $233 billion to Los Angeles County in 2014.
Garcetti is running for re-election on March 7 and will face 10 opponents. Challengers asked if he would promise to serve his full term.
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In response to the question, Garcetti said, "I never make promises," if people ask him to serve in another capacity, but "there's nothing else I'm focused on."
Also on the March ballot is Measure H, a county-wide quarter-cent sales tax for the homeless. It was billed as the companion to Measure HHH which passed overwhelmingly in November.
When asked what will happen if Measure H fails, Garcetti said it would slow down homeless housing efforts, and L.A. would end up making a dent, but not end homelessness.
On one of Garcetti's back-to-basics agenda items, he said water conservation was not over, despite the rainfall, and cutbacks helped keep down the water bill.
"Eyewitness Newsmakers" airs on ABC7 at 11 a.m. on Sunday.