The bus from Chennai to Nagercoil rammed into the stationary lorry at Samayapuram near here killing at least nine passengers of the bus on the spot, police said.
Those injured have been taken to a hospital. Of them, some are in a serious condition, police said.
The lorry was parked on the busy highway and it apparently did not have tail lamps switched on.
Top officials of the district administration and police were engaged in rescue operations.
Rescue teams were engaged in rescuing those trapped in the bus, police said, adding the driver of the lorry was absconding after the incident.
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