An Amtrak service travelling between New York and Miami with an estimated 139 passengers on board hit a CSX freight train, the Lexington Sheriff said.
The collision occurred near Charleston Highway and Pine Ridge Road, in Cayce, authorities said.
Several injured passengers were seen walking along the tracks after being evacuated, according to reports on social media.
The sheriff’s office said about 50 people were taken to hospital with injuries following the crash which happened at 2.30am local time (7.30am GMT).
A police spokesman said the injuries ranged from “scratches to more severe broken bones” but could not say whether any were life-threatening.
He added that no passengers or crew remained on the train. The Red Cross have set up a reception site at a local school.
In a statement, Amtrak said: “Amtrak Train 91 between New York and Miami came into contact with a CSX freight train at around 2.35am in Cayce, South Carolina.
“There were eight crew members and approximately 139 passengers, with injuries reported. Local authorities are on the scene responding. More information will be provided as available.”
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The collision is the company’s fifth crash this year and the fourth that resulted in deaths or injuries.
The accident comes days after an Amtrak train carrying several dozen Republican politicians, including US House Speaker Paul Ryan collided with a rubbish truck in Virginia, killing one person and injuring six others, including a congressman.