US Senate Democrats on Thursday blocked a resolution disapproving of the nuclear deal reached by world powers and Iran in July.
In a 58-42 vote, Republicans fell two votes short of the 60 needed to move forward the resolution, handing President Barack Obama a major victory in his foreign policy priority.
Obama said he was "heartened" that so many Senators judged this deal on the merits, and "gratified" by the strong support of lawmakers and citizens alike.
"Today, the Senate took a historic step forward and voted to enable the US to work with our international partners to enable the implementation of the comprehensive, long-term deal that will prevent Iran from obtaining a nuclear weapon," Obama said in a statement after the vote.
The P5+1 group -- the US, Britain, France, China, Russia and Germany -- reached a comprehensive nuclear deal with Iran in July. The accord would provide sanctions relief for Iran in exchange for limits on its controversial nuclear programme.
"This vote is a victory for diplomacy, for American national security, and for the safety and security of the world," the president added.
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Calling the vote a "tragedy", Senate Republican Leader Mitch McConnell said Democrats would pay a political price.
"This is a deal that will far outlast one administration. The President may have the luxury of vacating office in a few months, but many of our responsibilities extend beyond that," said McConnell, according to news website The Hill. "The American people will remember where we stand today."
"There are going to be more votes," Republican Senate Majority Whip John Cornyn told reporters, refusing to concede defeat."There will be other opportunities for people to change their mind next week, hopefully after they hear from their constituents."
US House Speaker John Boehner on Thursday pledged that Republicans would continue to make every effort to scuttle the Iran nuclear deal.
The debate on the nuclear agreement struck between world powers and Iran "is far from over," Boehner said at a press conference on the Capitol Hill before the Senate vote, vowing to "use every tool at our disposal to stop, slow, and delay this agreement."
"Republicans continue to do all that we can do to stop the president's nuclear agreement with Iran," said Boehner. "By putting party first, Democrats are ignoring the will of the American people and avoiding the judgment of history."
House Republicans are changing their strategy to voice their opposition to the deal, mulling the vote on a resolution stating the Obama Administration did not submit all the documents related to the Iran deal and therefore the 60-day congressional review period has yet to start.
They specifically refer to documents from the International Atomic Energy Agency (IAEA) on the Iran nuclear deal.
On Friday, House lawmakers will also vote on a measure to prevent the US from lifting sanctions on Iran.
After the Iran nuclear deal was reached, the Obama administration spared no effort to defend the accord and lobby Democrats to support it, arguing that it offered the best chance to prevent Iran from obtaining a nuclear weapon over the next decade.
Only four Senate Democrats defected. They are Charles Schumer, Ben Cardin, Bob Menendez and Joe Manchin.