The first chapel on the south side of the Co-Cathedral was dedicated to the Virgin Mary and was the first one to be given a particular devotion. The chapel housed one of the icons of the Virgin of Philermos that the knights had brought with them from Rhodes. The icon was believed to be miraculous and drew great devotion especially before battle when the knights would congregate and ask for the intercession of the Virgin Mary. When they returned victorious they would again congregate in the chapel in order to give thanks and present the keys of the conquered fortresses to the Virgin. The keys to the fortresses of Lepanto, Passava, Hammet and Patras are still present within the chapel.
When Napoleon expelled the Order from Malta in 1798, Grand Master Ferdinand Von Hompesch took it with him. The icon was taken to St Petersburg however its whereabouts remained unknown for several decades until it was rediscovered in Montenegro and is now exhibited in the Fine Arts Museum. The icon currently in the chapel depicts the Virgin of Lanciano known as the Virgin of Carafa. The Virgin of Carafa icon is housed in a reredos of precious marbles fitted during the reign of Grand Master Jean Paul Lascaris Castellar whose coat-of-arms is included in the altar. The inner sanctuary is enclosed by a silver gate installed in 1752. The walls were sculpted in 1659 with motifs of rich symbolic meaning, several of which were attributes of the Immaculate Conception and other titles of the Virgin Mary.