But times were barbarians[clarification needed], the sanctuary suffered thefts and administrative troubles, the senatorial families were dying out, while the institution had acquired a remarkable economic, no less than religious importance, and therefore had to be brought back under the control of the Bishop of Rome.

Once the Popes had returned to Rome from Avignon, first Martin V, then Nicholas V and Sixtus IV and finally Alexander VI put in order the management of the congregation and its assets, entrusting it entirely to the Confraternity, which was intimately linked to the Lateran Chapter and had become meanwhile a powerful economic entity.

Such merciful works exhorted the charity of the faithful to nourish them with new subsidies; and in fact, the memory of the generosity of Cardinal Giannantonio Sangiorgi from Piacenza, legate in Rome a latere during the absence of Alexander VI, as well as that of Julius II, who designated the Confraternite as heir of his assets, may be everlasting.".

The highly detailed Catasto annonario by Nicola Maria Nicolai (1756–1833) gives an overall picture of the agricultural properties belonging to the "Venerable hospital of the Holy Savior "ad Sancta Sanctorum" at the beginning of the 19th century.

After the war it was greatly expanded at public expense, through the construction of new wings inaugurated in September 1958 by the Christian Democrat Mayor of Rome Urbano Cioccetti – one of the main protagonists of the post-war urban planning of the capital – in the presence of the Ministers Fernando Tambroni and Giulio Andreotti.