Police have confirmed that a 35-year-old man from Newhaven died at the scene of the collision.
The collision happened near the junction with the A26 New Road and the B2109 Avis Road at South Heighton just after 10am.
A 65-year-old man from Bishopstone was taken to the Royal Sussex County Hospital in Brighton with serious injuries.
Both men were pedestrians.
The driver of the red dropside DAF lorry, a man from Kent, was uninjured. He was driving south on the A26 when the incident occurred.
Both the A26 and B2109 roads remain closed while investigation and recovery work takes place. It is hoped that the scene will be clear and reopened by mid-afternoon.
Anyone who witnessed the incident is asked to email firstname.lastname@example.org or call 101 quoting Operation Glinsk.