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The church and an adjacent convent and hospital were founded in 874 by Queen Angilberga, wife of the Emperor Louis II. The monastery became wealthy due the granting of significant privileges and properties in northern Italy. Over the centuries, several orders of monks and nuns competed for control of this monastery until 1425, when it was assigned to the Benedictine order of Monte Cassino. In 1499, they commissioned the present church from Alessio Tramello, which was consecrated in 1511.
The Benedictines stipulated that he must respect the existing foundations of the medieval church of San Sisto and incorporate the eight granite columns (which now support the vaults of the nave and aisles) remaining from an earlier project of 1494.
The church is a cruciform basilica with a barrel-vaulted nave of five bays flanked by aisles and outer chapels. The aisle bays are square and surmounted by domes; the arcade leading to the outer chapels is supported on cruciform piers, and each chapel consists of a straight bay with an apse. The main transept has apsed arms, but there is a second transept just behind the façade, with a central dome, and here the arms are planned as domed Greek crosses.
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