The aim of the present study is to collect the epidemic outbreaks and the epidemic waves of the bubonic plague of the Byzantine Empire during the first pandemic (541-751 AD). Human activities, such as trade and military movements have been speculated as underlying factors for the causation of the pandemic. Historical data combined with geographical spreading of the plague, allows an alternative speculation of suspicious enzootic areas in the Middle East. We conclude that the possible existence of enzootic areas in that region might have been responsible for the causation of the numerous outbreaks of the bubonic plague in the Eastern provinces of the Byzantine Empire during the 6th-8th century period.