In an open letter to the Islamic republic, the 47 Republicans, including Senate leaders and several potential 2016 presidential candidates, reminded Iranian leaders that President Barack Obama is in office only until January 2017, and a successor could scrap the agreement if Congress has not approved it.
"We believe that the letter has no legal value and is propaganda," Zarif said, quoted in Iranian media.
"The senators must know that under international law, Congress cannot change the content of the agreement.
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"Any congressional action to prevent the implementation of any agreement will violate the international commitments of the (US) government.
"The world is not just in America," Zarif added.
The letter appeared to be another bid to influence or even derail the talks underway between Tehran and the P5+1 group of world powers to rein in Iran's contested nuclear programme.
It marked a rare foray by Congress into US foreign policymaking, as negotiating with foreign governments is a responsibility typically handled by the executive branch, not lawmakers.