Top civil servant Sir Jeremy Heywood will be stepping aside for three months while he undergoes cancer treatment, the Cabinet Office has announced.
The Cabinet Secretary was diagnosed last summer and received treatment while continuing to work.
He is taking a leave of absence until September to have further treatment for the illness and a related infection.
Sir Jeremy was appointed Cabinet Secretary in 2011 and three years later also took on the role of head of the Civil Service.
National Security Adviser Sir Mark Sedwill will take over as Cabinet Secretary, the Prime Minister's most senior policy adviser, as well as continuing in his own post until September.
He will begin by chairing a regular meeting of Theresa May's top team on Tuesday morning.
John Manzoni, chief executive of the Civil Service, will take over Sir Jeremy's managerial responsibilities in Whitehall.
A Cabinet Office spokesman said: "Jeremy Heywood, Cabinet Secretary and head of the Civil Service, announced today that with the support of the Prime Minister he will be taking a leave of absence from his current role to have further treatment for the cancer diagnosed last summer and for a related infection."