The aim of this study is to present the sea and land commercial routes of the Byzantine Egypt and their role in the dissemination of the plague bacteria Yersinia pestis from the Red Sea to Mediterranean ports. The Mediterranean port of Pelusium was considered as the starting point of the first plague pandemic, according to the historical and archaeological data; the port of Clysma in the Red Sea, however, can also be assumed as possible entrance gate of the Yersinia pestis. Indeed, it is proposed that the port of Clysma is most likely to have been the gateway of Yersinia pestis in the Byzantine Egypt when the epidemic broke out, given its geographic position and close trade relationship at the time of the epidemic in Pelusium.