Secretary-General Ban Ki-moon says UNICEF chief Ann Veneman will not seek a second term.
Ban expressed "great regret" Wednesday that Veneman was stepping down and praised her "immense dedication ... and determination to improve children's health, education and well-being."
Before being appointed to head UNICEF in 2005, Veneman was the first female U.S. secretary of agriculture in the administration of U.S. President George W. Bush. Her term ends on April 30, 2010.
In a letter to friends and colleagues, Veneman said she was stepping down with "a heavy heart," but gave no reason for her decision.
The U.N. children's agency is active in 190 countries.