Pelusium was an ancient and fortified port city marking the beginning of the eastern Nile Delta. For this reason, the city was attacked many times during the Egyptian antiquity by Romans and Persians alike. By the 1st century, the city was already part of the Roman Empire, and [[Apostle Mark|Saint Mark]]'s preaching probably reached the region. Saint Epimachus of Pelusium is the first recorded saint from Pelusium, martyred during the Persecution of Decius (249–251).
Its first known bishop was Kallinicos during the Great Persecution of [[Diocletian]] (284–305), although it is not known if he was elected by the excommunicated [[
Melitius of Lycopolis]] (in that case he could not be listed as bishop) or adopted Melitius' [[Arianism|arianist]] heresy later on his episcopacy. Melitius' heresy consisted on his opposition to Saint Peter I's (300–311) readmission of lapsed Christians (who offered sacrifices to the idols when threatened by the Persecution) after some years of repentance. Melitius sided with Arius, but later had his excommunication lifted by [[Alexander of Alexandria|Saint Alexander]] (313–328).
His successor, Dorotheus, was present in the [[First Ecumenical Council]] in 325. Mark was exiled together with [[Athanasius of Alexandria|Saint Athanasius]] (328–373) in 335 by the Aryans for opposing their heresy. The Aryans replaced him with the heretical Pancratius, who was present in the Second Council of Sirmium in 351. Pancratius was probably the first Archbishop of Pelusium, since the city was made capital of Augustamnica Prima in 347. Ammon lived during the times of [[John Chrysostom|Saint John Chrysostom]] (398–404) and Eusebius the heretic seems to have been a Nestorian.