The only remaining hope for the White House and party leaders is to change opponents' minds. A showdown will come this week.
Collins' announcement comes as the Congressional Budget Office says the GOP bill would reduce health insurance coverage for "millions" of people.
Collins is the fourth GOP senator to come out against the measure. Arizona's John McCain, Kentucky's Rand Paul and Texas' Ted Cruz also say they oppose it, though Cruz aides say he's seeking changes so he can vote "yes."
All Democrats and independents will vote "no," so opposition by just three Republicans would kill the legislation.
The collapse of the effort would be another major setback for President Donald Trump and Senate GOP leaders.
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Maine's Sen. Susan Collins says she's against the last-gasp Republican health care bill. That means there are more than enough Senate GOP opponents to kill the party's drive to repeal President Barack Obama's health care overhaul.