Santo Spirito in Sassia is one of the relevant complex in the cultural heritage context of the center of Rome. Originally built on the command of the Saxon king to host his people during their pilgrimage to Rome, the structure includes the famous Sixtine Lanes, realized by some of the most prominent XVI century artists. These historical and valuable premises needed to be restored with a challenging task in the light of the high monumental value of the complex. The project documentation, made available by the St. Spirit Hospital Administration, owning the building, a preliminary study was conducted to define technical criticalities management strategies and project coordination, by virtue of the historical-monumental characteristics. The works regard the complete restoration of the artworks and structures, along with the reroofing of the edifice; the design proposed also the realization of an underground historical-educational path including the archaeological digs of Villa Agrippina. By means of a multidisciplinary operational approach to choose the best technical-economic option, the project rationalizes plants and technologies, for a respectful renovation of artworks without disturbing the regular activities of the compound, with particular attention to hospital tasks. The complex of S.Spirito in Sassia is protected according to L. 1089/1939 art. 1, 4 “Protection of things of artistic and historical interest” repealed by Italian Decree 42/2004 Code of cultural heritage and landscape.