Toby Lewis had been away from Sandwell and West Birmingham NHS Trust since last July but had been expected to return as chief executive, a post he has held since 2013.
However, the trust, which runs Sandwell General and Birmingham City hospitals and will also operate the new Midland Metropolitan University Hospital which is due to open in Smethwick next year, said he had now tendered his resignation.
He has decided to start work with London health charity the King's Fund.
Richard Beeken, the boss of neighbouring Walsall Healthcare NHS Trust, was brought into to help run the Sandwell trust in Mr Lewis' absence. Bosses said they would be searching for a permanent replacement.
Trust chair Sir David Nicholson said: “The trust chief executive, Toby Lewis has been off work unwell since summer 2020.
"He had planned to return after that. However, he has now decided to start work with the King’s Fund in London undertaking research and policy work on health inequalities and poverty, and has therefore, with regret, tendered his resignation.
“Richard Beeken remains interim chief executive and the trust will begin a recruitment process for a substantive Chief Executive shortly.
“We wish Toby well for the future and thank him for his service to our trust, our colleagues and the communities of Sandwell and West Birmingham.”
Mr Lewis was at the forefront of the effort the rescue the Midland Met project following the collapse of Wolverhampton construction giant Carillion which has contributed to it being way behind schedule.
He also led the trust’s initial response to the coronavirus crisis in early 2020.