Emergency services from Wanaka were called to the accident about 3pm. The crash was on a slight bend 3km south of the Cardrona village.
A witness who arrived just after the accident said a group of people attempted first aid on the man before emergency services arrived from Wanaka.
When they arrived, emergency services took over and performed CPR, but the man was pronounced dead a short time later.
Senior Sergeant Allan Grindell, of Wanaka, said it appeared the motorcyclist was heading south and had collided with the other vehicle in the northbound lane.
It was too early to know exactly what had happened and the police serious crash unit would be investigating.
An orange police cone about 30m from the accident site marked the distance debris from the crash had travelled.
An older woman who was one of the four occupants of the other vehicle was taken by ambulance to the Wanaka Lakes Health Centre as a precaution.
None of the other occupants were injured.
Police interviewed witnesses and those involved in the crash for more than an hour.
Snr Sgt Grindell said many of those who saw the accident were in shock and victim support would be offered. The road was closed to northbound traffic at the intersection of the Crown Range and State Highway 6 and to southbound traffic at the corner of Cardrona Valley Rd and Riverbank Rd.
Motorists heading towards Wanaka or Queenstown were told to take State Highway 6 past Cromwell.
The road was expected to be reopened last night.
Motorcyclists made up five of the 19 people killed on New Zealand roads this holiday period.
One motorcyclist was killed in a crash in the same period last year.
Last week, Scott Mackenzie, originally from Cromwell, died in a motorcycle accident near the town.
The official holiday period began at 4pm on December 23, and ended at 6am on Wednesday.
The latest Ministry of Transport figures showed 54 motorcyclists died on New Zealand roads in 2015.
A further 1181 motorcyclists were injured in crashes.
