At least two passengers were pulled alive from the crumpled wreckage as the rescue operation took place in the scorching heat.
Premier Matteo Renzi traveled to the scene, where prosecutors and investigators were at work trying to determine why two trains were on a single track.
Railway police Commander Giancarlo Conticchio told Sky TG24 said that the number of dead was 22 with 43 people injured, adding that the numbers could change.
"Surely one of the two trains shouldn't have been there. And surely there was an error. We need to determine the cause of the error," Conticchio said.
An aerial photo showed the cars crumpled together like an accordion, and forced off the tracks at sharp angles. The two trains, each with four cars, collided head-on in an olive grove on flat terrain between the towns of Andria and Corato.
The accident occurred around 11.30 AM some 50 kilometers (30 miles) northwest of the Puglia regional capital, Bari.
"I pulled him from under the debris, myself barefoot, from under the debris and metal," the woman, who was not identified, told local TV. "I went to my husband screaming. I pulled him by the legs and feet. I climbed past people in pieces, how sad. There was nothing I could do.
A woman who is eight months pregnant described being thrown forward.
Another survivor described the scene as "hell." Corato Mayor Massimo Mazzilli said debris was scattered all over the countryside.
"It's a disaster as if an airplane fell," Mazzilli said on his Facebook page, where he posted photos of the crash.
Premier Renzi pledged a thorough investigation. He returned to Rome from Milan to monitor the situation, and then traveled on to the scene of the accident. His transport minister, Graziano Delrio, as well as local prosecutors were at the scene.
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