Cabinet Secretary Simon Case has announced that he will step down by the end of the year due to health reasons.
The top civil servant had been undergoing treatment for a “neurological condition” for the past 18 months.
“My mind is motivated, but my body is not,” he said in a statement, adding that the decision was “solely for my health and has nothing to do with anything else.” he added.
Recruitment activities for the next Chief Cabinet Secretary have begun.
His role has already been advertised on the Civil Service website, with a salary of £200,000.
Mr Case, 45, told Sir Keir Starmer about his decision on Monday morning.
He has held the position since September 2020 and is currently serving as the fourth prime minister.
In a letter announcing his resignation, he said: “It has been an honor to serve two monarchs, four prime ministers and over 120 ministers in this role.”
He continued: “The world is changing rapidly and the civil service must change as well.”
He has been an unusually controversial figure at times, and has come under scrutiny over his role in the Downing Street political narrative and messages he has exchanged with ministers during the pandemic.
There have recently been reports of tension at the heart of No. 10 between Mr Case and the Prime Minister’s chief of staff, Sue Gray.
Last October, Mr Case announced he was taking a leave of absence citing personal health issues and was widely expected to leave the civil service in the coming months.
Mr Case, who graduated from the University of Cambridge with a PhD in political history, rose through the ranks after joining the civil service in 2006.
He held positions in the British intelligence agency GCHQ and in the Royal Family, reaching top jobs.
At 41, he became the youngest Cabinet Secretary in more than 100 years.
The Cabinet Secretary is the highest-ranking civil servant who advises the Prime Minister, leads the implementation of government policy, and is involved in the management of other senior civil servants.