Dame Barbara Stocking, chief executive of Oxfam, is to stand down in February.
A spokeswoman for the charity said Stocking, who has been in the position since May 2001, had not yet decided what she was going to do next, but was not retiring.
The spokeswoman said Stocking, who is 61, felt it was time to move on. "It was a good time for her and a good time for the organisation," the spokeswoman said.
In a statement, Stocking said: "I have loved leading Oxfam and would like to sincerely thank not only the thousands of dedicated staff working in some of the most difficult areas of the world, but also the public who have supported Oxfam in so many ways and campaigned tirelessly to help us achieve real change.
"I am looking forward to watching Oxfam continue its vital role as the voice of the millions of people unjustly living in poverty around the world."
Stocking, who worked in the NHS before joining Oxfam, was awarded a CBE for services to health in 2000 and made a Dame for humanitarian services in 2008.
The charity had an income of £385.5m in 2011/12 and employs 5,000 staff worldwide. It also has 22,000 volunteers.