Sants, 58, has been on sick leave since October due to stress and exhaustion. He was due to return in the new year, but Barclays today confirmed he has resigned with immediate effect.
In a statement, the bank said: "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."
Sants' departure comes less than a year after he took on the role of head of compliance, government and regulatory relations at the bank. He took the post on after five years as head of the FSA, throughout the financial crisis.
"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 Barclays chief executive Antony Jenkins.
"I know my colleagues will join me in expressing our appreciation to Hector, as well as wishing him a speedy recovery."
Sants' resignation comes a month after UNI finance, the union for the finance sector, warned of a "personal health crisis" in banking.
In late 2011, Lloyds Banking Group CEO Antonio Horta Osorio took time off for similar reasons, and in the same year Andy Hornby quit Alliance Boots less than a year after taking the post due to the stress of returning to frontline banking too soon after the collapse of HBOS.
The most severe case of banking sector stress occurred in July when 21-year-old intern Moritz Erhardt died after collapsing in the shower of his east London flat after working three consecutive all-nighters.
