Objectives: This work was designed to adapt Geographical Information System-based spatial analysis to the study of historical epidemics. We mapped "plague" deaths during three epidemics of the early 15th century, analyzed spatial distributions by applying the Kulldorff's method, and determined their relationships with the distribution of socio-professional categories in the city of Dijon. Materials and Methods: Our study was based on a database including 50 annual tax registers (established from 1376 to 1447) indicating deaths and survivors among the heads of households, their home location, tax level and profession. The households of the deceased and survivors during 6 years with excess mortality were individually located on a georeferenced medieval map, established by taking advantage of the preserved geography of the historical center of Dijon. We searched for clusters of heads of households characterized by shared tax levels (high-tax payers, the upper decile; low-tax payers, the half charged at the minimum level) or professional activities and for clusters of differential mortality. Results: High-tax payers were preferentially in the northern intramural part, as well as most wealthy or specialized professionals, whereas low-tax payers were preferentially in the southern part. During two epidemics, in 1400–1401 and 1428, areas of higher mortality were found in the northern part whereas areas of lower mortality were in the southern one. A high concentration of housing and the proximity to food stocks were common features of the most affected areas, creating suitable conditions for rats to pullulate. A third epidemic, lasting from 1438 to 1440 had a different and evolving geography: cases were initially concentrated around the southern gate, at the confluence of three rivers, they were then diffuse, and ended with residual foci of deaths in the northern suburb. Conclusion: Using a selected historical source, we designed an approach allowing spatial analysis of urban medieval epidemics. Our results fit with the view that the 1400–1401 epidemic was a Black Death recurrence. They suggest that this was also the case in 1428, whereas in 1438–1440 a different, possibly waterborne, disease was involved