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Senator John McCain has said he cannot support his fellow Republicans' latest effort to repeal Obamacare, dealing it a potentially fatal blow.
The Arizona senator, who is battling brain cancer, said he "cannot in good conscience" vote for the new plan, which President Donald Trump backs.
Mr McCain said it was wrong to pass such far-reaching legislation without input from the Democrats.
It is the second time he has thwarted his party leadership on the issue.
President Trump, speaking in Alabama late on Friday, condemned Republicans who did not back the new legislation, saying: "They don't have the guts to vote for it."
Republicans need 50 votes in a 100-seat chamber they control 52-48 to succeed.
With Democrats united in opposition, there is little margin for error.
Mr McCain's objection could doom conservatives' seven-year campaign to erase Democratic former President Barack Obama's signature legislative achievement.
In a statement on Friday, the Arizona senator said such a bill demands extensive hearings, debate and amendment.
"That is the only way we might achieve bipartisan consensus on lasting reform," he wrote, "without which a policy that affects one-fifth of our economy and every single American family will be subject to reversal with every change of administration and congressional majority."
Mr McCain said he could not support a rushed bill "without knowing how much it will cost, how it will effect [sic] insurance premiums, and how many people will be helped or hurt by it".
One other Republican senator, Rand Paul, is also against the party's latest bill.
Susan Collins indicated on Friday afternoon she may join the opposition.
The Maine senator said she was worried the legislation did not do enough to protect patients with pre-existing conditions.
"I'm leaning against the bill," Ms Collins said at a constituency event.
At least four other Republican senators are undecided: Lisa Murkowski, Dan Sullivan, Rob Portman and Jerry Moran.
Back to the drawing board
Analysis by Anthony Zurcher, BBC North America reporter
As several Republican senators explained - ones who were firm "yesses" - the main attraction for the plan was that it was the only plan on the table.
Now it appears Republicans will have to go back to the drawing board.
Although the end of September is the deadline for passing a bill with a simple majority in the Senate for this federal budget, there's no reason the party couldn't start the wheels turning for another vote next year - or, conceivably, simply change the rules, as Donald Trump has suggested.
None of that will alter the simple dynamic that made itself clear over the course of the past months, however.
The Republican Party, despite campaigning ferociously for Obamacare repeal for nearly seven years, could never agree on how to turn those promises into reality without sending the healthcare industry into a tailspin.
The Republican leadership had evidently hoped South Carolina Senator Lindsey Graham, one of the bill's authors, might be able to persuade his close friend Mr McCain to back the measure.
Undeterred on Friday, Mr Graham vowed: "We press on."
President Trump has been phoning lawmakers and state governors in a bid to tilt the scales in favour of the bill.
But several Republican governors this week also criticised the process as rushed, urging colleagues to abandon the proposal in favour of a slower, cross-party approach.
Sixteen major medical groups meanwhile issued a joint statement against the Republican legislation.
US Vice-President Mike Pence said on Thursday the so-called Graham-Cassidy bill was their "last best chance" to repeal Obamacare.
Senate Majority Leader Mitch McConnell was planning to bring the legislation to a vote next week, but it is unclear now if that will go ahead.
Republicans are still reeling from the collapse in July of their efforts to secure Senate passage of previous legislation to repeal Obamacare.
A dramatic late-night 'no' vote from Mr McCain - just days after he was diagnosed with an aggressive brain tumour - sunk that bill, too.
According to analysis released on Friday, if the Graham-Cassidy bill were to pass, 32 million fewer Americans would have health insurance by 2027.
And the non-partisan Brookings Institution said its findings "likely understates the reductions in insurance coverage".
The new bill, also drafted by Senator Bill Cassidy, would give states money in block grants to run their own healthcare programmes.
But critics say that when left to the states, the money going into the Medicaid programme for people on low incomes would diminish.
Republicans have long deplored Obamacare, known formally as the Affordable Care Act, as government overreach into the US healthcare system.
(BBC)
