Cochran used his considerable influence, including serving as chairman of the Senate Appropriations Committee, to direct billions of dollars to Mississippi.
"I regret my health has become an ongoing challenge," the 80-year-old Republican said Monday. His decision sets up a nonpartisan special election to coincide with the November general election.
Mississippi state Sen. Chris McDaniel, who nearly upset Sen. Thad Cochran in a bitter 2014 race, is teasing that he will mount a conservative primary challenge to Republican Sen. Roger Wicker.