Bobby Dean Johnson, 78, died around 9:50 a.m., according to Beaufort County Coroner Ed Allen.
Johnson's wife, who was in the car with him, was airlifted by helicopter to a Savannah hospital, Allen said.
Capt. Randy Hunter of the Bluffton Township Fire District said the woman is in critical condition.
Johnson was driving a Lexus sedan and pulled out from Pinckney Colony Road onto eastbound U.S. 278 into the path of a westbound pickup truck, S.C. Highway Patrol Lance Cpl. Hannah Wimberly said.
The pickup truck driver was not injured, she said.
All traffic on U.S. 278 was blocked for nearly two hours to accommodate the helicopter and clear the scene. All lanes were open before noon.