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The Eastern Cape Transport Department said four people were killed in a head-on collision on the R-63 outside Middledrift.
Spokesperson, Unathi Binqose, said the accident happened at around 13h30 on Sunday.
He said two people in a Toyota Urban Cruiser died on the scene while one person died on arrival at Grey Hospital.
Binqose said the second vehicle, a VW Polo, caught alight and the driver’s body recovered afterwards.
He said a case of culpable homicide was under investigation.
The names of the deceased have not yet been released.