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Romano-Byzantine era

The Roman general Pompey took over the whole of Cilicia and organised it as a Roman province in 64 BC. Adana was of relatively minor importance during this period, while nearby Tarsus and Anazarbus were more important metropolises. During the era of Pompey, the city was used as a prison for the pirates who frequently ravaged the Cilician coast and disrupted trade. A bridge over the Sarus (Taşköprü) was built in the early 2nd century, and for several centuries thereafter, the city was a waystation on a Roman military road leading to the East.

In the early period of Roman rule, Zoroastrianism, that had been introduced to the region by the Persians, was still observed in Cilicia as was Judaism which attracted many sympathisers. As home to some of the earliest Christian missionary efforts, Cilicia welcomed Christianity more easily than some other provinces.

After the permanent partitioning of the Roman Empire in 395 AD, the Adana area became a part of the Byzantine Empire, and was probably developed during the time of Julian the Apostate. With the construction of large bridges, roads, government buildings, irrigation and plantations, Adana and Cilicia became the most developed and important regional trade centres.

Adana became a Christian bishopric, a suffragan of the metropolitan see of Tarsus, but was raised to the rank of an autocephalous archdiocese after 680, the year in which its bishop appeared as a simple bishop at the Third Council of Constantinople, but before its listing in a 10th-century Notitiae Episcopatuum as an archdiocese. The Bishop Paulinus participated in the First Council of Nicaea in 325. Piso was among the Arianism -inclined bishops at the Council of Sardica (344) who withdrew and set up their own council at Philippopolis; he later returned to orthodoxy and signed the profession of Nicene faith at a synod in Antioch in 363. Cyriacus was at the First Council of Constantinople in 381. Anatolius is mentioned in a letter of Saint John Chrysostom. Cyrillus was at the Council of Ephesus in 431 and at a synod in Tarsus in 434. Philippus took part in the Council of Chalcedon in 451 and was a signatory of the joint letter of the bishops of Cilicia Prima to Byzantine Emperor Leo I the Thracian in 458 protesting at the murder of Proterius of Alexandria. Ioannes participated in the Third Council of Constantinople in 680. No longer a residential bishopric, Adana is today listed by the Catholic Church as a titular see.