The crash took place on Route 6 at about 8:30 this morning.
Wellfleet Fire Chief Richard Pauley said three people were transported to Cape Cod Hospital.
One lane of Route 6 remains closed just north of the Wellfleet Fire Department. Traffic is being diverted.
The head-on crash took place on Route 6 and Kerouach Road.
By the time the Wellfleet Fire department one driver was dead at the scene.
The preliminary investigation has determined that the operator of a Chevy van was traveling southbound on Route Six when it crossed over into the northbound lane at Kerouach Road striking a truck owned by R.W. Townsend & Sons.
The Chevy van then continued in the northbound lane striking another vehicle, a GMC Sierra pick-up truck.
The operator of the Chevy van, Wende Harrison, 54, of North Eastham, was pronounced dead at the scene.
The operators and a passenger from the other two vehicles were transported to Cape Cod hospital with non-life threatening injuries.
Both lanes of Route 6 were shut down for approximately 4 hours as traffic was re-routed down local roads.
At 12:30pm the northbound lane of Route Six was re-opened to traffic but the southbound lane remained closed as a crane was needed to lift a truck onto a flatbed tow truck.
In addition, Mass DOT officials needed to clean the debris field from the road and make appropriate roadway repairs.
By 2:30, one lane of the road was still closed.
At this time the accident remains under investigation by the Wellfleet Police department and the Cape Cod Regional Accident Reconstruction team.