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During his campaign for president, Trump called the agreement that the US and other world powers brokered with Iran "the worst deal ever negotiated."
After his election, he said he might try to renegotiate the 2015 deal, which places restrictions on its nuclear program for a period of time in exchange for sanctions relief.
But Ryan made that sound less likely, because the multilateral sanctions on Iran have largely been dismantled.
"Meet the Press" moderator Chuck Todd asked Ryan whether he'd like to "see the beginnings of trying to get out of the nuclear deal," and Ryan replied that "a lot of that toothpaste is already out of the tube."
"I never supported the deal in the first place," Ryan said, according to an advance transcript. "I thought it was a huge mistake. But the multilateral sanctions are done."
Ryan said he doesn't think the government is "going to go back and reconstitute the multilateral sanctions that were in place."
"I think we should expend our effort where it can pay off the most," Ryan said. "And that's why I think what they're doing now does make a lot of sense. So I think the key is to rigorously enforce this deal."
Ryan also suggested increasing sanctions, a step the Trump administration took on Friday.
The US Treasury issued a new wave of sanctions against Iran, targeting 13 people and 12 entities days after the White House put Iran "on notice" over its recent ballistic missile test and alleged involvement in an attack on a Saudi ship near Yemen.
The Treasury said the sanctions are "fully consistent with the United States' commitments" under the Joint Comprehensive Plan of Action, or the Iran nuclear deal.
"I think what this administration is doing, which I agree with, is saying, 'We have a new administration, and we're going to hold you, Iran, to account.'" Ryan told NBC. "This last administration did not do that. This new administration needs to do that. And I think that's what you're getting here."
Gen. James Mattis, Trump's secretary of defense, is also at odds with Trump over the nuclear deal. He said during his confirmation hearing that he supports leaving the deal in place.
"It is an imperfect arms control agreement - it's not a friendship treaty," Mattis said. "But when America gives her word, we have to live up to it and work with our allies."