The legislation, referred to as a "skinny repeal" bill, would repeal the Affordable Care Act's individual and employer mandates and temporarily repeal the medical device tax. The Congressional Budget Office scored the measure and found it will reduce the deficit from 2017 to 2026 by $142 billion.
Collins and Murkowski voted earlier this week against even starting debate on options to repeal Obamacare.
Dial back to a Trump tweet from the campaign, February 9, 2016: "We will immediately repeal and replace ObamaCare - and nobody can do that like me".
In addition, the bill would make it much easier for states to waive federal requirements that health insurance plans provide consumers with a minimum set of benefits like maternity care and prescription drugs.
The Affordable Care Act (ACA), known informally as Obamacare, brought insurance to 20 million previously uninsured Americans and was the signature domestic achievement of former Democratic President Barack Obama.
In response, Trump on Friday again suggested that his administration would let the Obamacare program "implode".
Trump has drilled into Republicans that they should take anything they can get when it comes to repealing Obamacare.
McConnell glanced in the direction of Senators Lisa Murkowski, R-Alaska, and John McCain, R-Ariz., when he said "most of us". While the GOP murmured "trust us" to some recalcitrant senators, promising that the House would not pass it anyway, the president was tweeting "Go Republican Senators, Go!" and health insurance coverage for an estimated 16 million Americans hung in the balance. Republican Senators Susan Collins from ME and Lisa Murkowski from Alaska had already declared that they would vote against the move, making Mr. McCain's vote decisive.
It is the third failed attempt to repeal Obamacare.
He claimed the current checks and balances are making the Republicans "look like fools" and called on the party's Senate leader, Mitch McConnell, to scrap the "outdated" rule.
There were gasps when Mr McCain, after being furiously lobbied by Vice-President Mike Pence, joined two other Republican senators in voting against the so-called "skinny" repeal plan, considered the bare minimum Senate Republicans could agree on.