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Donald Trump has hailed a vote to begin debate on healthcare reform as the "beginning of the end" of Obamacare.
Demonstrators interrupted the start of the make-or-break vote with shouts of "kill that bill, don't kill us" and "shame" as they stood in the visitors' gallery.
Senators voted to formally open debate on legislation to repeal much of the Affordable Care Act, introduced by President Trump's predecessor, Barack Obama.
The final tally was 51-50, with Vice President Mike Pence breaking the tie.
Obamacare repeal debate protests: 'Kill that bill!'
Mr Trump, who made repealing and replacing Obamacare a key plank of his successful White House bid, said the vote was a "big step".
He said his predecessor's healthcare reforms, passed in 2010, "should have been terminated a long time ago".
One of those who voted to begin debate was Arizona senator John McCain, who returned to Congress for the first time since being diagnosed with brain cancer and was given a standing ovation.
The 80-year-old had a visible scar above his left eye after having a blood clot removed earlier this month.
Senator McCain returned to vote just days after being diagnosed with brain cancer
Mr Trump earlier called on Republicans to "step up to the plate" on the issue after "seven years of talking".
Senate Majority Leader Mitch McConnell urged colleagues in his party, which controls both chambers of Congress, to vote in favour of moving forward on the legislation.
Democratic leader Chuck Schumer urged senators to reject it, saying: "Turn back now before it's too late."
The development sets up days of debate and votes, and it is unclear whether ultimately there will be enough votes to pass whatever bill is presented to Congress.
May: Trump step closer to scrapping Obamacare
In a sign of the difficulties the Trump administration will face getting a bill passed, Senator McCain said after the vote that he would not vote for the legislation as it stands.
A number of other Republicans are known to be sceptical about how Mr Trump's replacement could affect millions of Americans.
John Cornyn, the Senate Majority Whip, adopted a conciliatory tone after the vote, calling on Democrats to help improve the bill.
