Sen. Bill Cassidy’s political career is at stake on Saturday as Louisiana voters weigh in on the Republican for the first time since he voted to convict President Donald Trump in his 2021 impeachment trial.

Cassidy, a two-term senator, faces a primary challenge from Trump-backed Rep. Julia Letlow and state Treasurer John Fleming, who have both pitched themselves as more Trump-aligned alternatives. If no candidate gets majority support Saturday, the top two finishers will head to a runoff on June 27.

Cassidy acknowledged in an interview with NBC News last month that his impeachment vote “might” be a liability in the race. But he insisted he works well with Trump and highlighted his record of getting legislation passed and signed into law, drawing a contrast with his opponents. He also has the backing of Senate GOP leadership.

“Bill Cassidy has been a terrific senator for Louisiana,” Senate Majority Leader John Thune told reporters Thursday. “Our job is to do what we can to support incumbents — but obviously the voters of Louisiana are going to make that decision.”

The day before the primary, Trump posted on Truth Social in support of Letlow, though he steered clear of attacking Cassidy in the way he did a few weeks ago.

“I know Julia well, have seen her tested at the highest and most difficult levels, and she is a TOTAL WINNER!” the president wrote. “A Proud Mother of two children, Julia is a wonderful person, has ALWAYS delivered for Louisiana, and would continue doing so in the United States Senate.”

The ranks of Republicans who backed impeachment for Trump after the Jan. 6, 2021, Capitol riot were never big to begin with, but they are dwindling in Congress. Among the 10 House Republicans who voted to impeach Trump in 2021 and the seven Senate Republicans who voted to convict him, only three subsequently won re-election. And all of them ran in all-party primary scenarios, allowing them to reach beyond traditional Republican voters for support.

In Louisiana, Gov. Jeff Landry, who is backing Letlow, signed legislation changing state primaries from “jungle,” all-party races to more traditional party primaries ahead of Cassidy’s race. Landry also delayed all of Louisiana’s House primaries that were scheduled for Saturday to give state lawmakers time to redraw congressional maps there, after the Supreme Court struck down the current district lines.

The Senate primary stayed on its original date. Altogether, Cassidy says Landry is creating an uphill battle for him in the election.

On a call with reporters Friday, Cassidy asserted that the closed primary is making it more difficult for unaffiliated voters to vote for him.

“People are calling my office to say they tried to vote for me, but they could not. ” Cassidy told reporters on a call Friday. “People are confused … It’s a terrible system for this election.”

“It’s not an accident that voters are confused by this intentionally difficult process,” Cassidy campaign manager Kate Larkin wrote in a statement shared with NBC News. “The Governor closed the primary and continuously meddled in this election to support Julia Letlow.”

But as the Republican electorate measures him against Letlow and Fleming, Cassidy, a physician and the chair of the Senate Health, Education, Labor and Pensions Committee, is contending with the fact that impeachment is not the only time he has found himself out of step with the Trump administration.

Cassidy has publicly clashed with Health Secretary Robert F. Kennedy Jr. over his vaccine skepticism, though the senator also cast the key vote to install Kennedy in his position.

Earlier this month, Trump blamed Cassidy for standing in the way of his nominee for surgeon general, Casey Means, with opposition forcing the president to replace her with a new pick. Means, who Cassidy said did not have the votes to get confirmed, is a wellness influencer and a close ally of Kennedy’s.

These conflicts have made Cassidy a target of Kennedy’s “Make American Healthy Again” movement, too. A group called MAHA PAC has spent hundreds of thousands of dollars aimed at replacing Cassidy with Letlow.

Overall spending has topped $30 million. According to AdImpact, an ad-tracking service, ads in support of Cassidy have totaled $21.8 million, with another $9.8 million in ads boosting Letlow and $1.5 million in spending on pro-Fleming ads.

Letlow has leaned heavily into the MAHA message in the closing weeks of the campaign, while Cassidy has attacked Letlow over her stock trades and past support for diversity, equity and inclusion efforts when she was working at the University of Louisiana.

Cassidy has characterized the race as “Letlow’s to lose,” but he has expressed confidence that he will ultimately win re-election no matter what happens with a potential runoff race.

“She is the person to beat,” he said on a call with reporters in early May, adding that if Letlow “doesn’t make the runoff ... then I would be in against Dr. Fleming, and we would have accomplished our mission.”

Fleming has stayed in the race, despite Trump’s endorsement of Letlow. He also claimed he was offered a Trump administration job to drop out, which he says he declined.

Fleming has tried to marshal grassroots support by focusing his campaign on concerns about the state’s carbon capture policies, and he has billed himself as the only “true conservative” in the race.

While Trump may have waded into the race, other Republicans have stayed on the sidelines — including House Speaker Mike Johnson, a fellow Louisiana Republican.

“Julia is like a sister to me. We’re very close,” he told NBC News earlier this week. “My awkward situation is I’m also close to the other candidates. John Fleming was my predecessor and was the first person who endorsed me to take this seat, and of course I’ve worked well with Sen. Cassidy.”