Nancy Pelosi, the Democratic former House speaker, and George W. Bush, the Republican former president, do not agree on much. But earlier this year, they joined a high-powered gathering in Washington — with the Irish rock star Bono on video from Dublin — to mark the 20th anniversary of America’s biggest and, arguably, most successful foreign aid program.

Mr. Bush created that program, the President’s Emergency Program for AIDS Relief, in 2003. In the two decades since, PEPFAR, as it is known, has saved 25 million lives and served as a powerful tool for soft diplomacy, a symbol of America’s moral leadership in the world. It has had extraordinary support from a bipartisan coalition of liberals and Christian conservatives.

But now PEPFAR is in danger of becoming a victim of abortion politics — just as the State Department is reorganizing to make the program permanent.

The program is set to expire at the end of September. But House Republicans are not moving forward with a bill to reauthorize it for another five years, because abortion opponents — led by a G.O.P. congressman who has long been a supporter of PEPFAR — are insisting on adding abortion-related restrictions.

The stalemate is the latest example of how Republicans are using their majority in the House of Representatives to impose their conservative views on social policy throughout the federal government. They have focused in particular on abortion, a year after the Supreme Court overturned Roe v. Wade and, with it, the right to legal abortion. Earlier this summer, House Republicans loaded up the annual military policy bill that has long been bipartisan with provisions to limit abortion access and transgender care.

The fight over PEPFAR, a $7 billion-a-year program that operates in more than 50 countries, is similar, because it is a broadly bipartisan program that now appears at risk of being sucked into a partisan fight over cultural and social issues.

PEPFAR continues to have wide support, including from Representative Michael McCaul of Texas, the Republican chairman of the Foreign Affairs Committee, which oversees the program and approve the reauthorization legislation. But so far, Mr. McCaul has not advanced it because of the objections of abortion foes, including his Republican colleague, Representative Christopher H. Smith of New Jersey, one of the leading anti-abortion voices in Congress who also helped draft the legislation creating PEPFAR.

Mr. Smith now says he will not agree to renew the program unless it is subject to the so-called Mexico City policy — enacted by Republican presidents but lifted by Democrats, including President Biden — that would bar the program from partnering with any organization that provides abortion services, no matter the source of the funding.

That is a non-starter for Democrats, who are demanding a “clean” five-year reauthorization — one with no added policy restrictions.

“We’ve done clean reauthorizations for 20 years,” said Representative Barbara Lee, Democratic of California and a chief sponsor of PEPFAR.

But there is a substantial stumbling block: Three influential outside groups that oppose abortion — the Family Research Council, the Heritage Foundation’s political action arm and Susan B. Anthony Pro-Life America — have sided with Mr. Smith and intend to “score” the vote when they compile their annual ratings of members of Congress. A vote for renewing PEPFAR without the anti-abortion language would be counted as a demerit, making it politically toxic for most Republicans.

The situation has alarmed champions of the program. In an email, Bono called the impasse “madness,” and called on Congress to “protect the bipartisan commitment to keeping politics out of PEPFAR.”

Mr. McCaul said he is “talking to supporters both inside and outside the government, and working with my colleagues on both sides of the aisle in the House and the Senate” to resolve the dispute. He has also been texting with Bono, who in turn has been in touch with congressional leaders on the matter.

A senior White House official, speaking on the condition of anonymity to describe the negotiations, said on Thursday that the White House was “engaging closely with Congress at senior levels” in pursuit of a straight five-year reauthorization.

The program is an important legacy for Mr. Bush and other Republicans of his era, including Bill Frist, the former Senate majority leader, and Rick Santorum, a former senator from Pennsylvania.

“I look back on the things I did as a member of Congress, and feel like I was able, as the pro-life warrior in the United States Senate, to forge a compromise to get conservatives to support this,” Mr. Santorum said in an interview. “It’s been a great thing for our country, and it’s been a great thing for humanity.”

Last week, Mr. Santorum publicly pleaded for a “five-year, clean extension” in an opinion essay in the conservative outlet Newsmax. He said he intended to use Congress’s upcoming August recess to try to forge a compromise.

But in recent months, Mr. Smith, the New Jersey Republican, and right-wing groups have begun accusing the Biden administration of injecting progressive politics into the program.

In late May, a Heritage Foundation scholar published an essay in The Hill arguing that PEPFAR had become “increasingly politicized” and needed an overhaul. Mr. Smith followed in early June with “Dear Colleague” letter asserting that Mr. Biden had “hijacked PEPFAR.”

In an interview, he pointed to new language in a PEPFAR country and regional operational plan calling for the program to partner with organizations that advocate for “institutional reforms in law and policy regarding sexual, reproductive and economic rights of women.” He argued that was code for a plan to “integrate abortion with H.I.V./AIDS work.”

The document also says PEPFAR programs should “advance human rights and decriminalization for lesbian, gay, bisexual, transgender, queer, and intersex (L.G.B.T.Q.I.+) communities.” That did not sit well with the Family Research Council, whose chief lobbyist, Travis Weber, recently called PEPFAR “a massive slush fund for abortion and L.G.B.T. advocacy.” In an interview, he said he stood by those words.

The senior White House official said that the “intentional focus on health equity is new” and that it came in response to requests from local communities for PEPFAR to “address barriers to health for children, adolescent girls and young women, and key populations.” The mention of women’s rights refers to ensuring that adolescent girls have access to schools, the official said.

The Biden administration has added a footnote to the document clarifying that PEPFAR does not fund abortions, an assertion that Mr. Smith called “meaningless.”

There is no evidence that PEPFAR or its foreign partners have used federal tax dollars to promote or perform abortions; U.S. law does not allow it. But some PEPFAR grantees, such as Population Services International, a global health nonprofit based in Washington, do provide abortion-related services with money from other sources.

“The assertion is made by critics is that organizations like P.S.I. are working with U.S. money and involved in abortion — and shouldn’t that be illegal?” said Karl Hofmann, the group’s president and chief executive. “I guess my answer is, those two facts are true, and it’s not illegal.”

Ms. Lee, the California Democrat, said she is working to “clarify this misrepresentation” being made by Mr. Smith.

But the prospects for a five-year extension seem bleak.

“We are in a very precarious place,” said Shepherd Smith, an evangelical Christian and a co-founder of Childrens AIDS Fund International, a nonprofit. He has organized other faith-based groups to issue a letter in support of reauthorization.

Christopher H. Smith, the New Jersey congressman, has proposed an alternative: He persuaded fellow Republicans to insert language into a State Department spending bill that would allow PEPFAR to keep operating for a year without a new authorization, but subject to the anti-abortion restrictions. But even if that were to pass, certain programs — including one devoted to orphans and vulnerable children — would lapse after Sept. 30.

And the symbolism of such a move would be devastating, PEPFAR’s backers say — a signal to other nations that the United States is abandoning its bipartisan commitment to end the AIDS epidemic by 2030, and that Washington is truly broken. It would also be a setback for global health; PEPFAR has created an infrastructure of clinics in poor nations that provide other services, including Covid-19 testing and vaccines.

“This is not an issue that at all involves abortion — it’s about having health care facilities in countries to deal with pandemic type of challenges,” said Senator Benjamin L. Cardin, Democrat of Maryland. He called PEPFAR’s creation “one of the great moments in American foreign policy.”

As the debate plays out on Capitol Hill, the State Department official who oversees PEPFAR, Dr. John N. Nkengasong, is about to get a big promotion. On Tuesday, Secretary of State Antony J. Blinken is expected to announce the establishment of a new Bureau of Global Health Security and Diplomacy, to be led by Dr. Nkengasong. The idea is to integrate PEPFAR into the department’s broader global health work and to transition it out of emergency status.

Since its inception, the program has invested more than $100 billion in fighting the global AIDS crisis. Independent analyses by K.F.F., formerly the Kaiser Family Foundation, have found that PEPFAR has helped improve maternal and child health and is “associated with large, significant declines in mortality” in countries where it has operated.

Backers of the program are hoping that Mr. Bush will weigh in. Earlier this year, Emily Bass, an author and activist, sent the former president a signed copy of her book, “To End a Plague: America’s Fight to Defeat AIDS in Africa,” which chronicles the PEPFAR story.

A few weeks ago, Ms. Bass said, Mr. Bush sent a letter thanking her.

“Laura and I will remain invested in this mission for the rest of our lives,” he wrote.