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Four people, including a toddler, have died in a single-vehicle accident on the N2 about 30 kilometres from Makhanda.
The Eastern Cape Transport Department said two other passengers in the VW Polo sustained serious injuries.
Spokesperson, Unathi Binqose, said the jaws of life had to be used to extract those trapped in the front of the car which he said overturned after hitting "a concrete slab" on Saturday afternoon.
He said the deceased were the male driver, two adult females, and a toddler.
Binqose said one of the two females who was injured was airlifted to a hospital in Gqeberha while the other woman was rushed to a hospital in Makhanda.
Police have opened a culpable homicide docket.