Lord Darzi was one of several "goats" in Gordon Brown's cabinet
Top surgeon Lord Darzi, one of several non-political figures brought into Gordon Brown's government, is to resign as health minister.
Downing Street confirmed he will remain as a government adviser but quit as a minister "to devote more time to his clinical role and academic research".
Lord Darzi was among experts in various fields who joined the PM's "government of all the talents" - dubbed "Goats".
Lib Dem Norman Lamb said it was a "massive blow for Gordon Brown".
Last year Lord Darzi published his review setting out plans for the next 10 years of the NHS in England.
In his resignation letter he said he had overseen the implementation of his report's conclusions and was "deeply grateful" for the chance to serve in the government but now wanted to step down as a minister.
"As you know, I have maintained my busy clinical practice and research contributions during my time as a minister. The time has now come for me to return to care for my patients, lead my academic department, and continue my research on a full time basis," he wrote.
He will officially resign when Parliament goes into recess later this month but No 10 said he would take on a new role as health and life sciences ambassador.
In a statement, Downing Street said the prime minister had thanked him for an "outstanding contribution" as a health minister.
"He will take on a new role as a health and life sciences ambassador for the government and will chair a new NHS Global forum to promote the NHS and the UK's life-sciences industry around the world," it said.
"Lord Darzi will also advise on health reforms in both the NHS and our global public health."
Of the other "Goats" to join Gordon Brown's government in 2007, the foreign office minister Lord Malloch Brown, is due to stand down at the end of July, former CBI boss Lord Digby Jones quit as trade minister last year and former Ofcom boss Lord Carter recently signalled his intention to quit as minister for communications and broadcasting.
But Lord West, the former First Sea Lord, remains as security minister.
Shadow health secretary Andrew Lansley said: "This was surely coming for a long time. Ara Darzi's laudable focus on quality was increasingly at odds with the Brownite fixation with targets and command and control".
Liberal Democrat health spokesman Norman Lamb said: "Losing yet another minister will be a massive blow to Gordon Brown.
"As a respected doctor, Darzi led the initiative on the NHS for Labour and questions must be asked on whether there is more to his resignation than meets the eye.
"A short spell as a minister seems to be the new route into the House of Lords for New Labour supporters."
Niall Dickson, head of the health think tank the King's Fund, said Lord Darzi's "personal commitment" had been crucial in driving forward NHS plans to improve quality of care and deliver better value for money.
Dr Peter Carter, chief executive of the Royal College of Nursing, said: "Lord Darzi has been instrumental in shifting the focus of health reforms to where they should be, which is on providing quality care.
"He leaves a lasting legacy on the health service and it will be important to continue to focus on quality and safety and not to let financial pressures take centre-stage over the coming months and years."