Sir Hector Sants, Barclays' head of compliance and former boss of the Financial Services Authority (FSA), is leaving the bank.
Mr Sants had been on sick leave since the beginning of October, suffering from stress and exhaustion.
He was due to return in the New Year, but has decided to resign instead.
Sir Hector joined Barclays in January this year. Before that he was head of the Financial Services Authority from July 2007 until July 2012.
From 2010 to 2012 he was also deputy governor designate of the Bank of England and chief executive designate of the Prudential Regulation Authority.
He is the latest top banking executive to suffer from stress. Lloyds Banking Group chief executive Antonio Horta-Osorio was forced to step away from his role temporarily in 2011 for similar reasons.
In a statement, Barclays said: "Hector Sants has been on sick leave since the beginning of October, suffering from stress and exhaustion. He has concluded that he will not be able to return to work in the near term. Consequently he has decided to resign from Barclays and not return from sick leave."
Sir Hector's role at Barclays was to take responsibility for ensuring the bank's 140,000 staff obey the law in the 50-plus countries in which it operates.
"Although only with us for 10 months, he has made significant progress towards creating a world class compliance function at Barclays and in improving our relationships with regulators and governments," said Antony Jenkins, Barclays' group chief executive.
"I know my colleagues will join me in expressing our appreciation to Hector, as well as wishing him a speedy recovery."
The bank said Allen Meyer, the current head of compliance for corporate and investment banking, would act as interim head of compliance and government and regulatory relations.
In a separate senior management change, Barclays also announced that it was losing chief operations and technology officer, Shaygan Kheradpir, who is taking up a chief executive role in the US.
Barclays said that Darryl West, currently the bank's chief information officer, would act as interim group chief operations and technology officer.