Mike Nesbitt has resigned as health minister amid a row with the UUP leader Jon Burrows.
The decision comes following a clash over withdrawing emergency general surgery services from Causeway Hospital.
Nesbitt served twice as leader of the party, first from 2012 until 2017 and again from 2024 until earlier this year when Burrows took over.
In a statement, a UUP spokesperson thanked Nesbitt for his service and said he left a "significant legacy".
Nesbitt is the second high-profile resignation from the party within months, after another ex-leader Doug Beattie quit in May, lashing out at Burrows' leadership.
Last week Burrows, who is a North Antrim MLA, told a town hall meeting that he did not support emergency general surgery being removed from Causeway Hospital.
The position appeared at odds with the Department of Health's policy on the matter, after the Northern Health Trust previously recommended that EGS should only be provided at one of its hospital sites.
Nesbitt was unable to attend due to a constituency election meeting in Strangford.
UUP leader Jon Burrows attended in his place.
He voiced opposition to the closure of the EGS service. Last Wednesday, Burrows said he did not agree with that and would "never agree with it".
"Emergency surgery must remain at the Causeway Hospital and it should be built up, not run down and that is my position and it's not for negotiation."
However, he stopped short of saying whether or not he would direct Nesbitt not to sign off on the move.
'A significant legacy'
In a statement on Tuesday, a UUP spokesperson confirmed Nesbitt's resignation.
"We thank him sincerely for his service and for the leadership he has given to our health and social care workforce," they said.
"Mike took on one of the most difficult briefs in government with a genuine determination to make health and social care better for everyone in Northern Ireland.
"From beginning the shift towards a neighbourhood model of care, to putting health inequalities at the centre of policy, he leaves a significant legacy, not least the progress made on some of Northern Ireland's longest waiting lists."
It is unclear who will take over as health minister. The UUP said it will set out further details on next steps shortly.
Nesbitt's decision to quit leaves the party seven days to nominate a replacement.