Philip Rycroft, who once said fears about Brexit "keeps me awake at night", is due to step down as permanent secretary at the Department for Exiting the European Union (DexEU) within weeks.
Mr Rycroft, 57, is the latest in a string of senior figures to leave DexEU, and his departure sparked claims from critics that the "chaotic" Brexit department was struggling to cope with the demands of leaving the EU.
His predecessor Olly Robbins moved to the Cabinet Office to lead talks with Brussels, while Brexit secretary Stephen Barclay became the third person in post after both David Davis and Dominic Raab resigned in protest at Theresa May's Brexit plan.
Announcing his departure, cabinet secretary Sir Mark Sedwill said Mr Rycroft had demonstrated "exceptional leadership" and has "a deep understanding of the practical and policy challenges and opportunities of Brexit".
Mr Barclay said: "I would like to thank Philip Rycroft for his excellent leadership of the department, initially as second permanent secretary and subsequently as head of the department since October 2017.
"Under Philip's guidance, the department has been at the heart of the Government's preparations for a smooth and orderly exit from the European Union, and to deliver the mandate of the people."
He will be replaced by Clare Moriarty, the permanent secretary at Defra, who said it was an honour to lead the department at such an important time for the UK.
His departure drew criticism from pro-EU campaigners.
Labour MP Jo Stevens, who backs the People’s Vote campaign, said: “The chaotic Brexit department is already on its third secretary of state, and now we learn they’ll soon be onto their third permanent secretary as well.
"The department is a reflection of the whole Brexit process – shambolic and doomed to fail.”
And Liberal Democrat Brexit spokesman Tom Brake said: “So the only managed departure the Department for Exiting the European Union has been able to strike is for their own permanent secretary.
“I wish Philip Rycroft well in his retirement, albeit I am sure the public, like me, would prefer to see the whole Brexit shambles retired instead.
“With a change in personnel at this key stage in the Brexit process, questions will be raised. The best assurance Ministers could give is to back the Liberal Democrat campaign to give the people the final say, including the option to stay in the EU.”
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