The crash happened on a straight stretch of the line near Lodi, about 50km south-east of Milan, at around 5:30 am local time.

The two dead were the train's drivers. The Region of Lombardy, which encompasses Milan, said a further 31 people were hospitalised, including four with serious but not life-threatening injuries.

Lodi Prosecutor Domenico Chiaro said he was focusing his investigations on a mispositioned railroad switch on which maintenance work was done overnight.

"Had the switch been straight, the train would not have derailed," he said in a press conference.

"It was not in a position guaranteeing the train's free passage."

"We are looking at the possibility of a human error [...] a human error that might be linked to the maintenance work" on the switch, Chiaro added.

The Frecciarossa ("Red Arrow" in Italian) was cutting through the open countryside at around its top cruising speed of 300 kilometres per hour when something went wrong.

Footage from the crash showed a heavily damaged engine lying sideways, on the other side of a depot facing the track, and pointing in the opposite direction from the rest of the train.

The scene was "visually devastating," Pietro Foroni, Lombardy's Civil Protection Commissioner, said in comments broadcast by the SkyTG24 news channel.

The Frecciarossa can carry up to 900 passengers, but Lodi Prefect Marcello Cardona said that there were only 33 people on board, with four in the first three carriages.

"This avoided a more serious tragedy," he said.

Traffic on the high-speed rail line south of Milan - one of Italy's busiest - was suspended, with trains cancelled or rerouted to slower tracks, causing delays of up to one hour.

Meanwhile, railworkers' trade unions said what happened was "unacceptable" and announced a two-hour strike starting Friday at noon.

Australian Associated Press