Dr. Chris Eagle, in a statement, said he was stepping down effective immediately as president of Alberta Health Services.
"This is a personal and very difficult decision, but it is one that is right for me and for our organization," said Eagle in the statement.
"I have spent the last three years leading AHS, the largest health care authority in the country, and it has been my privilege to have had that opportunity."
Alberta Health Services handles front-line care as a stand-alone entity, but ultimately answers to Horne and his department.
Dr. John Cowell, the chief administrator of the organization, said chief financial officer Duncan Campbell will take over while the search begins for a replacement.
Cowell told reporters Eagle will stay on until October 2014 doing various other projects, adding there will be no severance pay.
The change is coming at a good time "in that we are about to embark on a new (streamlined) organizational structure, Cowell said.
"I can tell you there's outstanding buy-in."
The resignation is more upheaval for Alberta Health Services, which was created in 2008 as the province's health regions were amalgamated under one board in order to reduce costs and increase efficiency.
Since then, the system has been wracked with organizational shakeups and blowups. There have been documented cases of bureaucratic infighting, turf wars and lavish pay deals for senior managers. There have been scandals over queue-jumping and doctor intimidation.
Eagle took over from the first president, Stephen Duckett, who was heavily criticized for reports that emergency room waits had become so bad, patients were suffering for 20 hours or more waiting to be seen, while others dialled 911 for paramedic help while sitting a few feet from the admitting desk.
Four months ago, Horne fired the entire Alberta Health Services board for refusing his directive to rescind executive pay bonuses.
Last week, Eagle was forced to apologize to home care clients who were denied service due to problems with contracted providers in Edmonton.
The board was replaced by Janet Davidson, an executive with Edmonton's former Capital Health region, who has since begun the organizational overhaul.
Horne, in a news release, said: "On behalf of government, I thank Dr. Eagle for his service to our province and personal commitment to the care of Albertans."
Wildrose critic Shayne Saskiw says in the years of turmoil, the only constant has been Horne.
"We've seen under Minister Horne the health-care system brought to complete chaos," Saskiw told reporters.
"When you fire a board of a multibillion-dollar entity, (and) when you have the CEO step down, you know there are serious problems."
Liberal health critic David Swann, himself a medical doctor, said Eagle struggled as best he could in a situation where political meddling was constant but meaningful change was not.
"My surprise is that (Eagle) has lasted this long, frankly," said Swann.
"It's a blow again to the stability and the trust in our health-care system, and it's a demonstration that this government is lurching from crisis to crisis."
Guy Smith, head of the Alberta Union of Provincial Employees, said the roller-coaster must end.
"Front-line employees can't have confidence in their organization when there are constant questions about its leadership," said Smith in a news release.
"Since (AHS's) inception that clear leadership has been missing, and it has been to the detriment of the quality of our health care."
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