Health minister Lord Warner has resigned and will leave his job at the end of the year.
Lord Warner has said that, at 66, he wants to "spend more time with his family and not his red boxes."
Downing Street has denied that it is linked to the troubled plan to update IT infrastructure across the NHS, which the minister was overseeing.
The prime minister called Lord Warner "outstanding minister". His replacement will be announced in the new year.
Lord Warner was appointed as special adviser to Jack Straw, when he was home secretary, after Labour's 1997 election victory.
The following year he was made a life peer and the chairman of the Youth Justice Board for England and Wales, a post held for five years.
He was made health minister in 2003.