Moments after Manchin announced his support, Senate Majority Leader Harry M. Reid told The Washington Post "I feel pretty good" about eventual passage of the ENDA.
"I've talked with Democrats and Republicans, and I think we've got 60 now," he said.
The proposal would be the most significant piece of gay-rights legislation passed by Congress since the repeal of the military's "don't ask, don't tell" ban on gays in uniform in late 2010. But supporters have struggled for years to pass the bill.
It cleared the Democratic-controlled House in 2007, but faced filibuster threats in the Senate. Six years later, prospects for passage in the Democratic-controlled Senate have improved markedly, but the bill is all-but dead in the Republican-dominated House. That makes any Senate vote mostly an attempt by Democrats to score political points ahead of next year's midterm elections.
Asked about using this bill as a political maneuver, Reid said: "I only run the Senate, I don't run the House."
Another moderate Democrat, Sen. Mark Pryor (D-Ark.), said he would vote "yes" for the bill Tuesday night. His support is notable considering that he faces a difficult reelection next year in a politically red and socially conservative state.
The fresh Democratic support comes with about a week to go until Reid begins holding votes on the bill, giving supporters just a few more days to ensure that ENDA has the 60 needed to clear procedural hurdles.
The measure currently has 54 co-sponsors -- 52 Senate Democrats and two Republicans, Sens. Susan Collins (Maine) and Mark Kirk (Ill.). In addition to Manchin and Pryor (who are not co-sponsors), Sens. Orrin Hatch (R-Utah) and Lisa Murkowski (R-Alaska) also voted for ENDA when it was passed by the Senate Health, Education, Labor and Pensions Committee in July.
That takes the vote total to 58.
On Thursday Sen. Cory Booker (D-N.J.) takes over the seat of the late Sen. Frank J. Lautenberg (D-N.J.) and gay-rights activists say he also will vote for the plan.
That takes the vote count to 59 -- still one vote short.
So who's left?
Most of the attention is focused on Sen. Rob Portman (R-Ohio), who told reporters Tuesday that he's "inclined to back" the proposal. A spokesman later clarified that Portman "agrees with the underlying principle" of the measure, but is seeking changes to address concerns with the bill's religious liberties provisions.
Supporters are also targeting a handful of Republicans who have previously supported gay-rights legislation and policies: Sens. Patrick J. Toomey (R-Pa.), Kelly Ayotte (R-N.H.), Dean Heller (R-Nev.) and Jeff Flake (R-Ariz.).
But Flake said in a statement late Tuesday that even though he supported a 2007 version of the measure, the new Senate version "includes new provisions that will increase the potential for litigation and compliance costs, especially for small businesses. For that reason, I oppose the Senate bill."
Spokespersons for Toomey, Ayotte and Heller said Tuesday that their bosses are still reviewing the legislation and remain undecided.
Gay-rights groups, led by the Human Rights Campaign, have spent about $2 million on lobbying efforts, including the deployment of 30 field organizers to seven states represented by wavering senators. The outreach has included more than 108,000 e-mails sent to supporters, tens of thousands of phone calls, postcards and in-person visits with potential supporters who have been urged to call their senators.
Rallying GOP support has also been an early test for the American Unity Fund, a group led by hedge fund executive and GOP mega-donor Paul Singer that has spent about $500,000 on similar outreach, according to organizers. As The Post's Peter Wallsten reported last week, American Unity Fund has been quietly prodding Republican lawmakers to expand their support for gay rights by using a "yes" vote on ENDA as their first step. The group is using new polling data and talking points to coach would-be supporters on how to discuss gay rights without alienating core conservative supporters.
The vote also will be a big test for the White House, which has used executive actions to advance federal policy on gay rights and pushed hard for the repeal of "don't ask, don't tell."
Senate aides and gay-rights activists caution privately, however, that President Obama is unlikely to enjoy any sway over wavering senators and that any active lobbying might spoil chances of passing the bill. (Gay-rights groups are also upset that Obama has yet to sign an executive order requiring federal contractors to immediately protect gay and transgender employees from workplace discrimination.)
Asked Monday whether Obama plans to actively lobby for passage of ENDA, White House Press Secretary Jay Carney said that "There’s obviously a lot of work still to be done, but he absolutely hopes and expects the Senate to act and pass this legislation and will encourage continued movement through the Congress."
Sen. Rand Paul (R-Ky.) intends to place a hold on the nomination of Janet Yellen to be the next Fed chair.
One of the main contractors for HealthCare.gov warned the Obama administration weeks before the Web site launched about problems.
HHS Secretary Kathleen Sebelius will testify before a House committee Wednesday.
Sen. Ted Cruz (R-Tex.) said Obama is "abusing his power."
Cruz is headed back to South Carolina next week.
Sen. Dick Durbin (D-Ill.) removed a Facebook post that claimed a GOP leader told the president, "I can't even stand to look at you."
New Jersey Gov. Chris Christie (R) is not committing to serving out all of a second term.
Support for the death penalty has declined to a 40-year low.
"Controversies show how Obama’s inattention to detail may hurt his presidential legacy" -- Scott Wilson, Washington Post
"Obama accused of breaking promise to consumers as health plans cancel policies" -- Lena H. Sun and Sandhya Somashekhar, Washington Post
"6 Questions Sebelius Can Expect From the GOP" -- Matt Fuller and Steven Dennis, Roll Call
Juliet Eilperin contributed to this report.