In a statement, police said emergency services were called to the scene on Glenorchy-Routeburn Rd just after 4.40am after two vehicles had collided.
"Sadly, one person died at the scene," police said.
Police staff, including the Serious Crash Unit, are at the scene and the road is partially blocked.
There are no available diversions and the road is partially opening when possible.
'A tragic 48 hours'
In the wake of the latest serious crash this weekend, Inspector Sarah Thorn, District Road Policing Manager, issued a "firm message", urging drivers to slow down, stay alert and make safe driving choices as traffic increases in the South over the coming week.
The message follows a tragic weekend, with two fatal crashes in Southern District between 7am Friday and 7am this morning.
The other fatal crash occurred in Port Chalmers, while there were critically injuries in an Outram crash and serious injuries in a motorcycle accident near St Bathans.
"Our staff have been busy with several other serious injury crashes that were also attended during this period," Insp Thorn said.
"There are quite simply too many crashes happening on our roads, and the consequences can be devastating."
The coming days are expected to be particularly busy on Southern District roads, with Waitangi Weekend travel combined with the annual Burt Munro Challenge motorcycle festival, being held in Invercargill from February 4-8.
The Burt Munro Challenge attracts several thousand participants, spectators and visitors from across New Zealand and overseas.
It is expected to significantly increase traffic volumes throughout the wider Southern District.
