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The 65-year-old Republican from Tennessee announced his decision on Tuesday. Corker, who was first elected in 2006, said he told people then that he "couldn't imagine serving more than two terms."
"I also believe the most important public service I have to offer our country could well occur over the next 15 months, and I want to be able to do that as thoughtfully and independently as I did the first 10 years and nine months of my Senate career," the senator said in a statement.
The vacancy in Tennessee opens a long-shot opportunity for Democrats in a traditionally red state. Trump easily won the state in last year's presidential election with more than 60 percent of the vote.
GOP Sen. Lamar Alexander and Corker easily won their 2014 and 2012 re-elections, respectively, with more than 60 percent of the vote.
Corker is the chairman of the Senate Foreign Relations Committee. Trump reportedly considered him for secretary of State.
Corker pointedly criticized Trump last month after the president's defiant response to violence at a white supremacist rally in Virginia. Trump "has not yet been able to demonstrate the stability nor some of the competence that he needs to demonstrate in order to be successful," Corker said at the time.
Trump later responded by saying Tennessee was "not happy" with Corker. He tweeted that the senator "is constantly asking me whether or not he should run again in '18."
The senator was asked Tuesday morning by CNBC about reports of his possible retirement.
"It's been a tremendous privilege to do what I've been doing, it remains that," Corker said. "I look forward to being in the center of this tax reform debate, so many issues are coming up, as you know Iran likely will be at the forefront again in October. I'm busy doing my job – I will share the plans with you at the right time, maybe very soon."
The last Tennessee Senate election without an incumbent took place in 2006. Corker defeated former Rep. Harold Ford Jr. by a margin of about 51 percent to 48 percent.