Authorities were called to US 25 near Duncan Chapel Road around 6:20 PM on Saturday.
A pickup truck was traveling north on US 25 when a Toyota traveling south crossed into the north bound lane.
Two adults and two children in the pickup truck were taken by EMS to Greenville Hospital.
The driver of the Toyota and one of the passengers both died at the scene. The driver had to be mechanically extracted.
Another passenger from the Toyota died later at Greenville Hospital.
There are no charges.