The lack of valid demographic data and the literary ambiguities of the Byzantine chroniclers raise questions about the actual size and mortality rate of the Black Death in the Byzantine Empire. This study presents for the first time a quantitative overview of the Black Death in Byzantium for the period 1347-1453. Our data were obtained from descriptions of the plague, by prominent Byzantine historians and scholars, grouped by time of appearance and geographical spread. During the period 1347-1453, a total of 61 plague reports were noted, which can be distinguished in nine major epidemic waves, 11 local outbreaks and 16 disease-free periods. The capital Constantinople and the Venetian colonies of the Ionian and Aegean Sea were the areas most affected by the plague. The epidemic waves of the Black Death in Byzantium had a total average duration of 3.2 years. Scientific ignorance of the nature of the disease, a turbulent period of warfare and an organized maritime network seem to have contributed to the spread of the disease. Employing quantitative analysis, our multidisciplinary study sheds light from various standpoints on the evolution and dynamic of the plague in the South-eastern Mediterranean during the 14th and 15th centuries, despite the lack of sound morbidity and mortality data.