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The former Indiana senator, who was a considered a strong candidate to serve as President Barack Obama's running mate in 2008, is expected to announce Monday that he's jumping into the race for Republican Sen. Dan Coats' seat, a source close familiar with the plans told CNN.
The report was later confirmed by NBC News and Politico.
Coats is not seeking reelection.
CNN reported that Baron Hill, the current Democratic nominee, will announce he's stepping out of the race later Monday as well.
Bayh served two terms as governor of Indiana and later as a senator from the state before stunning many and deciding against running for reelection in 2010. Obama's 2008 campaign manager David Plouffe later wrote it was a "coin toss" between Bayh and Biden for the vice presidency.
Coats' seat was not considered a likely state to flip from Republican control over to the Democrats before news of Bayh's announcement broke.