Reverend Martin Smyth, Ulster Unionist MP for South Belfast, is to stand down at the next election.
The 73-year old, an opponent of the 1998 Good Friday Agreement, told his constituency party at an annual general meeting last week he wished to spend more time with his ill wife Kathleen.
Esmond Birnie and Michael McGimpsey, a pro-Agreement Assembly member, are seen as the leading candidates to be selected to replace the veteran politician, an MP since 1982.
Mr Smyth was elected in a by-election after his friend Rev Robert Bradford was assassinated by the Irish Republican Army.
A successor will be chosen on February 24th.
Speaking on his possible successor, Mr Smyth said voters in South Belfast wanted a politician opposed to further concessions to Sinn Fein.
Should the UUP select a pro-Agreement candidate, the main Protestant party in Northern Ireland, the Democratic Unionist Party, is likely to put forward a candidate to contest the seat.
"South Belfast was an open contest," the DUP said in the wake of Mr Smyth's announcement.
In 2000, Mr Smyth unsuccessfully stood against David Trimble for the leadership of the UUP, despite securing 348 votes (43 per cent) in the 860-strong Ulster Unionist Council.
He resigned the party whip in June 2003 with Jeffrey Donaldson and David Burnside over opposition to power sharing.
The UUP has a 5399 majority in South Belfast. The Catholic SDLP won second place with 9,601 votes (24.3 per cent).