In the run-up to the 2001 UK general election McGimpsey challenged sitting MP Martin Smyth for the Ulster Unionist nomination for Belfast South and gained 43% of the valid poll. In light of anti-agreement Smyth's selection the then anti-agreement Democratic Unionist Party did not stand a candidate, but the pro-agreement Progressive Unionist Party was prompted to put one up. McGimpsey, however endorsed Smyth.
2005
In 2005 the sitting UUP MP Martin Smyth retired and McGimpsey was selected as the official UUP candidate for the south Belfast constituency in the 2005 general election following a close selection campaign against an unknown figure, Christopher Montgomery. The Democratic Unionist Party, for the first time in over twenty years, stood a candidate in the form of former policeman Jimmy Spratt. In the battle between the two Unionist parties, both Smyth and former Ulster Unionist leader James Molyneaux appeared in a photograph with Jimmy Spratt which was included in his election literature. While Smyth subsequently claimed that this was "just a photo" that did not constitute an endorsement, "two Ulster Unionists had let it be known in the most public fashion that they preferred an unknown DUP candidate to the man selected by their own party". When the results were declared the poll was split three ways, with Social Democratic and Labour Party politician and part-time GP, Alasdair McDonnell winning the seat. Such an eventuality had been anticipated before the election in discussions between the UUP and DUP about an election pact involving Fermanagh and South Tyrone and Belfast South amongst other constituencies. David Burnside is known to have favoured the pact benefiting Tom Elliott, as he felt that Elliott could unite Unionists in Fermanagh and South Tyrone more readily than McGimpsey could in South Belfast.
2010
In December 2009, McGimpsey ruled himself out from standing in South Belfast in the 2010 General Election, saying that he felt he would best serve his constituents by continuing to work as Minister for Health.
2007 Assembly election
In the Assembly election of March 2007 McGimpsey retained his seat but the UUP's vote in South Belfast fell from 27.0% in 2003 to 18.4% of the popular vote in 2007, which resulted in the party losing its second seat, originally held by Esmond Birnie, which was picked up by Anna Lo of the Alliance Party
McGimpsey was politically close to David Trimble and at once talked of as a future leader of the Ulster Unionist Party, however he has never been a potential or actual challenger to a UUP leadership election. Politically McGimpsey is seen as being on the left of the Ulster Unionists and is a member of the Unionist Labour Group.