Martinez already had said he would not seek re-election, but had fended off rumors that he would give up the seat early.
His decision puts Republican Gov. Charlie Crist - who is running to replace Martinez - in charge of filling the seat in the interim.
In a letter to friends and supporters obtained by The Associated Press, Martinez says he's stepping down early for personal reasons.
"My priorities have always been my faith, my family and my country, and at this stage in my life, and after nearly 12 years of public service in Florida and Washington, it's time I return to Florida and my family," Martinez wrote.
The note says his resignation will be "effective on a successor taking office to fill out the remainder of my term."
Martinez announced in December that he would not seek a second term in 2010, also citing a desire to spend more time with his family.
He denied that he faced difficult re-election prospects in a state won by President Barack Obama. But he has struggled to boost public support because of his close ties to President George W. Bush and his efforts pushing an immigration bill that was unpopular with many Republicans.
Martinez was elected in 2004 after serving as the U.S. secretary of housing and urban development during the Bush administration. He served as general chairman of the Republican National Committee for 10 months, resigning in October 2007.
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