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Socio-economic vulnerability plays a major role in affected countries by disasters and emergencies. This study aims to identify the most effective socio-economic vulnerability indicators on COVID-19 cases and severity in the Yazd city. This study was conducted in 2022. Regarding purpose of study, different methods were applied during this research. They were including reviewing scientific research, expert panel sessions, weighting the socio-economic vulnerability indicators by Analytic Hierarchy Process (AHP) and examining the spatially relationships between vulnerability indicators and COVID-19. Excel and GIS software were applied for data analysis using local correlation coefficient. AHP analysis showed that employment, population density, buildings quality and distance from hospitals were obtained the most weight in the related indicators of socio-economic vulnerability. GIS mapping overlying showed that four socio-economic vulnerability sub indicators including percentage of immigrants, age, population density and distance from health centers had spatially relationships with COVID-19 cases and severity. Western, northern and some central regions of Yazd were identified as the COVID-19 hot spots. Local officials and health authorities should pay immediate attention to the most influential socio-econimic vulnerability indicators that are dominant in the Yazd city. They incorporate measures to the regions identified as hot spots because people who located in these areas are more vulnerable to COVID-19 and the other future natual or man-made disasters., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier Ltd.)