It had a regular staff of 13, a Master who held overall responsibility and 6 nuns and 6 monks.
In 1450 an unpopular advisor to the king, Bishop Adam Moleyns of Chichester was conducting a service at the chapel of Domus Dei when a number of naval seamen (resentful of being only partially paid and only provided with limited provisions) burst in to the church dragged out the bishop and murdered him.
As a result of this the entire town of Portsmouth was placed under the Greater Excommunication, an interdict which lasted until 1508, removed at the request of Bishop Fox of Winchester. One of the conditions for the removal of the interdict included the building of a chantry chapel next to the hospital.
In 1540 like other religious buildings it was seized by King Henry VIII and until 1560 was used as an armory. After 1560 it became the home of the local military governor. Throughout this time the chapel attached to the hospital remained in use and in 1662 it hosted the wedding of King Charles II and Princess Catherine of Braganza.
Towards the end of the 17th century it fell into disrepair until it was restored in 1867 to bevome the Garrison church.
On January 10, 1941 the buildings of Domus Dei were destroyed in an attack by German bombers.