"It's time for me and my family to move on to the next chapter in our life," Thompson said at a news conference a few hours after giving his formal resignation to the president.
Thompson used the news conference to tout what he said was a long list of accomplishments in his tenure as head of a department that oversees a broad range of health-related issues, not once mentioning the political controversy that accompanied many of them.
"We touched the third rail of politics," he said, referring to the landmark Medicare legislation that passed Congress a little more than a year ago.
"We turned America's attention to disease prevention," he said. "And we're waging a bold new global fight against HIV AIDS." He also referred to the shortage of flu vaccine as well as his efforts to respond to the threat of anthrax.
Mark McClellan, the government's Medicare chief and brother of White House press secretary Scott McClellan, is Thompson's likely successor, officials said.
Thompson's resignation brings to eight the number of members of Mr. Bush's 15-member Cabinet who have left. He said he would serve until Feb. 4 or until the Senate confirms his successor.
News of Thompson's departure came not long after the president formally announced former NYPD commissioneras his choice to replace Tom Ridge as secretary of Homeland Security.
A day earlier, Mr. Bush announced that he had chosento be secretary of Agriculture, replacing Ann Veneman.
Also Thursday, U.N. Ambassadorafter just five months on the job. He had been mentioned as a possible successor to Secretary of State Colin Powell, but Mr. Bush picked Condoleezza Rice instead.
Danforth says he plans to retire.