"No," Buttigieg said when asked by CNN's Jake Tapper on "State of the Union" if he would seek to succeed retiring Democratic Sen. Debbie Stabenow.
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Buttigieg had previously indicated he would not pursue the seat, citing his current focus on his job in President Joe Biden's Cabinet, but had stopped short of ruling it out altogether.
"I'm planning to vote in that election as a resident of Michigan, but look, the job that I have is, first of all, I think, the best job in the federal government," he told Tapper on Sunday.
"This job is taking 110% of my time, and obviously I serve at the pleasure of the president. But as long as he is willing to have me continue doing this work, I'm proud to be part of this team," Buttigieg added.
Buttigieg, the former mayor of South Bend, Indiana, moved last year to Michigan, where the parents of his husband, Chasten, live.
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Democrats are defending 23 of the 34 Senate seats on the ballot next year, including three seats in states that backed former President Donald Trump by at least 8 points in 2020: West Virginia, Montana and Ohio.
Besides Michigan, the party is also defending seats in other battleground states such as Arizona, Nevada, Pennsylvania and Wisconsin.
Potential Democratic candidates for Stabenow's seat include Reps. Elissa Slotkin and Debbie Dingell, and state Sen. Mallory McMorrow, who drew national attention last year in a floor speech pushing back against anti-LGBTQ attacks from a Republican colleague.
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