Independent Senator Kyrsten Sinema of Arizona has announced she will not run for re-election in November.
She decided to leave the Senate “because I choose civility, understanding, listening, working together on stuff”, she said.
Ms Sinema switched from being a Democrat to an independent in 2022 but typically votes with her former party.
This sets up a straight fight between Republicans and Democrats, who narrowly control the upper chamber.
It is unclear which party benefits more from her announcement.
While her departure means the Democrats lose a senator who votes with their party, some Democratic strategists fear a three-way fight in November.
Ms Sinema was expected to face a tough re-election campaign running this year.
Both Democrat Ruben Gallego, currently serving in the House of Representatives, and Republican Kari Lake, a former local news presenter backed by Donald Trump, sought to unseat her. Now they will likely go head-to-head in the general election.
The outcome could decide which party controls the Senate.
Democrats currently hold a tight majority with the Senate’s three independents – Ms Sinema and Senators Bernie Sanders and Angus King – aligned with the party.
“The only political victories that matter these days are symbolic, attacking your opponents on cable news or social media,” Ms Sinema said in a video announcing her departure.
“Compromise is a dirty word.”
Ms Sinema has been in office since 2019 and consistently broke with her party to side with Republicans on legislation or to confirm appointments made by then-President Donald Trump.
She is best known for her opposition to changing rules around the Senate filibuster, a tool used by the minority party to block legislation.
Democrats had sought changes to the chamber’s rules to avoid the filibuster and use their majority to boost access to abortion and change election rules.
Facing criticism from Democratic colleagues and voters, the former member of the Green Party announced in December 2022 that she would serve as an Independent.
Recent polls have shown her lagging behind her competitors. After her announcement on Tuesday, Ms Lake praised her for standing “tall against the Far-Left in defense of the filibuster” and Mr Gallego thanked her for her service and asked voters to reject Ms Lake and her “dangerous positions”.
West Virginia’s Joe Manchin, a conservative Democrat who also refused to change Senate rules to pass his party’s priorities, is set to leave the chamber when his term ends in January, as well.
But Ms Sinema, the first openly bisexual member of the Senate, was not just known for her moderate positions and her disputes with her Democratic colleagues.
She gained national recognition for wearing bright, colourful clothing on the often-staid Senate floor.
She also donned wigs during the pandemic to call attention to social distancing, saying that it was her way of avoiding getting a haircut.
