In an open letter to the Islamic republic signed by 47 lawmakers, they told Iran any deal signed by Obama must be ratified by Congress or it could be abandoned by any future president.
The letter appeared to be another bid to derail the talks underway between Tehran and the P5+1 group of world powers to place Iran's nuclear programme under international surveillance.
Many Republican senators fear such a deal would loosen economic sanctions on Tehran while leaving it free to secretly attempt to develop nuclear weapons technology.
The letter, published online last night by Bloomberg, notes the need for the US Congress to approve of international treaties -- by a significant majority -- to make them law.
It says "we will consider any agreement regarding your nuclear-weapons programme that is not approved by the Congress as nothing more than an executive agreement between President Obama and Ayatollah Khamenei," referring to Iran's supreme leader.
"The next president could revoke such an executive agreement with the stroke of a pen and future Congresses could modify the terms of the agreement at any time," it warned.
"President Obama will leave office in January 2017, while most of us will remain in office beyond then -- perhaps decades," it warned.
The letter was also signed by most of the Republican party's probable 2016 presidential contenders.
Dealing with foreign governments is a responsibility typically handled by the US executive branch and not lawmakers.
But, following heightened unease over the nuclear negotiations, the Republicans invited Israeli leader Benjamin Netanyahu to speak to Congress last week about the Iranian threat.
Obama administration officials called the invitation a breach in diplomatic protocol, and Democrats said the speech was "condescending.
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