Cabinet secretary Sir Jeremy Heywood is to step down until September to receive further treatment for cancer.
His responsibilities will be split between national security adviser Mark Sedwill and civil service chief executive John Manzoni.
Heywood was first diagnosed with cancer last summer and remained in post during a previous round of treatment which continued until early Autumn 2017.
A Cabinet Office spokesperson said Heywood would now be receiving further treatment for this cancer, and a related infection.
The spokesperson added: “The prime minister has asked Sir Mark Sedwill, the national security adviser, to assume Sir Jeremy’s formal responsibilities as cabinet secretary through to September. John Manzoni, chief executive of the civil service, will lead on issues relating to the management of the civil service until Sir Jeremy returns in September."
Sedwill will continue to carry out his duties as national security adviser.