Collins, the pilot of the shuttle Discovery's return to flight mission last year, plans to pursue private interests and spend more time with family.
"Eileen Collins is a living, breathing example of the best that our nation has to offer," said NASA Administrator Michael Griffin. "She is, of course, a brave, superb pilot and a magnificent crew commander. Beyond those qualities, she is both very bright and modestly self-effacing about that fact.
"And above all," added Griffin, "she is possessed of a quiet determination to attain the very highest levels of accomplishment. I am proud to know her and will greatly miss her at NASA."
A veteran of four space flights, Collins was selected as an astronaut in 1990 and went on to become the first woman selected as a pilot astronaut, the first woman to serve as a shuttle pilot and the first woman to command a U.S. spacecraft.