The 63-year-old announced his retirement as South West Coast's representative in Spring Street on Monday morning, bringing his nearly three decade-long political career to an end.

Dr Napthine's resignation will trigger the first by-election in the region since 1983, when former prime minister Malcolm Fraser retired.

Polwarth MP Terry Mulder has also resigned, after representing the constituency since the 1999 state election.

The outgoing South West Coast MP told The Standard it had been an honour to represent the region in State Parliament.

"Twenty-seven years as local member is a long time," Dr Napthine said. "As far as I'm concerned, I've always put the interests of the electorate first.

"It's been an absolute honour and privilege to represent this great area in the State Parliament. 

"I've also had the honour of being the minister in two different governments (Kennett and Baillieu) and being premier of the state. But first and foremost, my fundamental responsibility has been to listen to the local community, work with the local community and seek to improve services, opportunities, the economy."

The former premier told The Standard his decision to stand down as South West Coast MP was taken after consultation with his wife Peggy and family. He also notified State Opposition Leader Matthew Guy some time ago.

"I'm now well into my 60s and I've served a long time," he said. "I think it's appropriate for south-west Victoria to have some fresh blood, somebody who is equally passionate, I hope, about our region, who loves our region as much as I do.

"Somebody who can work hard with the community in the lead-up to the 2018 state election."

South West Coast is held by the Liberal Party on a margin of nearly 11 per cent while Polwarth is held by the same party on a 10.6 per cent margin.