As early as 1881, the 17th-century Carmelite convent of Maria in Trastevere was used as a prison. After adaptation works directed by Carlo Mangini, it kept the name Regina Coeli and was inaugurated in 1900. The complex also included the Women's Prison of the Mantle, the Criminal Records Office and the Political Police School. During fascism it also became a political prison, which housed Alcide De Gasperi among others.

Following the occupation of the city, the third and sixth arms were managed by the SS. This is where many of the dead of Forte Bravetta and the Fosse Ardeatine came from; but also the 320 deportees of 4 January 1944. and not far away is located the Military College, where the Jewish victims of round-ups from the raid of 16 October 1944 were taken.

Several anti-fascists were imprisoned there, including politicians, military personnel and intellectuals. More than 2,500 inmates arrived, when the planned capacity was 900. On 28 December 1943, the GAP man Mario Fiorentini threw a bomb that caused three deaths;

Epic was the escape of Pertini and Saragat on 24 January 1944. The two future presidents were arrested on 18 October 1943 and taken to Via Tasso.They were then taken to the sixth wing of Regina Coeli where they had been. Later in mid-November they were sentenced to death.

Transferred to the third wing with some Badoglian officers, they managed to escape with five other political prisoners thanks to a plan devised by Giuliano Vassalli and Peppino Gracceva, commanders of the clandestine Roman Socialists, later to become the Matteotti Brigades, with the help of Massimo Severo Giannini and Ugo Gala, who prepared a false release order.

A crucial role was played from inside the prison, by the lawyer Filippo Lupis, who pretended to be a police officer; and by the doctor Alfredo Monaco, who together with his wife arranged a hiding place after the escape. On 3 February, Leone Ginzburg died there, having been arrested in the clandestine printing works of Italia Libera. Also detained there were the fascists who had voted for Grandi's agenda pending the trial in Verona; and those of the Palazzo Braschi gang, arrested by the Germans for their robberies.

After the war, director Donato Carretta was lynched by the mob. On 18 September, during the trial against Police Commissioner Pietro Caruso, he was recognised and assaulted. Carretta was beaten, dragged over the rails of the tramway line to run him over and finally thrown into the Tiber. His corpse was later recovered and hung from the bars of a prison window.