A tablet found in 1753 in the church of St. Peter, indicates that Ditarius, bishop of Acqui, died on 25 January 488, in the Consulate of Dinamias and Syphidius.

In the list of the bishops of Acqui appears Saint Guido (1034–70), who was said to be a member of the family of the Counts of Acquesana,[7] under whose patronage the cathedral was erected.

[9] In 1068 the new city of Alessandria, named in honor of Pope Alexander III, was created, with the object of countering the political maneuvers of the Emperor Frederick Barbarossa.

In 1180, Archbishop Algisius of Milan, acting on authority delegated to him by Pope Alexander, decreed the union of the two dioceses in the person of Bishop Uberto Tornielli of Acqui, who would take the title of Bishop of Alessandria, but the arrangement was acceptable neither to the people of Acqui nor to Bishop-elect Otto of Alessandria, and therefore the union did not take effect.

[14] Bishop Uberto, however, was caught in some simonical transactions with regard to churches in both dioceses which were not under episcopal control, and he was suspended by Innocent III from his functions on 12 October 1211.

Pope Innocent VII (Roman Obedience) appointed Fra Bertolino of Alessandria as the new bishop on 14 April 1405.

1340) held a diocesan synod which concluded on 10 April 1308, and issued, with the consent of the Cathedral Chapter, a set of canons which were concerned mostly with clerical conduct and the proper administration of the sacraments, as well as limitations on the participation of lay persons in the election or installation of clergy.

On 13 April 1475 he wrote to Bishop Thomas de Regibus of Acqui, naming him papal Nuncio and Collector of Papal Revenues in the entire Marquisate of Monferrat, and granting him the powers necessary to make the collection from all church institutions (including Chapters, monasteries, Priories, and convents) and persons (from Patriarchs and Archbishops down to simple clerics), administrators, and officials, both exempt from normal episcopal jurisdiction and not exempt; lay persons were to contribute 3 ⅓%, and Jews 5%.

Pope Sixtus IV in response ordered the Archpriest of the neighboring diocese of Asti to investigate the matter.

[23] A diocesan synod was held by Bishop Ludovico Bruni (1499–1508), and a set of thirty-nine canons of entirely traditional content was published from the Cathedral of Acqui on 22 August 1499.

[27] His hagiographical life, with perhaps some exaggeration, says that he built the Cathedral of S. Maria with his own funds, and had Bishop Petrus of Tortona and Albertus (Obertus) of Genoa consecrate the edifice on 11 (or 13) November 1167.

A new agreement to prevent this dereliction of duty was sworn to with Bishop Constantinus Marenchi on 11 October 1486, binding both those canons who were present and those who happened to be absent from the meeting.