Police Superintendent Jorge Raineri said the small car carrying a nephew of the pope along with the man's wife and two young children slammed into the back of a truck. The wife and children, one 2 years old and the other 8 months, were killed.
The pope's 38-year-old nephew Emanuel Bergoglio, the son of a brother of Pope Francis, was hospitalized.
The accident occurred between the cities of Rosario and Cordoba, apparently as the family was returning to Buenos Aires following a holiday weekend.
Vatican spokesman the Rev. Federico Lombardi said "the pope was informed about the tragic accident. He is deeply pained." He added the pope asks "all who share in his grief to unite with him in prayer."