Most of the dead were passengers on the train, which derailed, Tunisia's transport ministry said.
Both drivers were also killed.
The interior ministry said the train was heading into the capital from the town of Gaafour, 120 kilometres to the south-west, in the morning rush hour.
The collision happened near El Fahes, some 60 kilometres from Tunis, around 6:30am local time (3:30pm AEST).
"The death toll could rise," transport minister Mahmoud Ben Romdhane told Mosaique FM radio.