Background: Malaria remains endemic in Comoros. In 2006, malaria was the leading cause of mortality, morbidity and consultation in hospitals. The Government of the Union of the Comoros is committed in the fight against malaria through the establishment of a National Strategic Plan in 2007 that was later updated for the period 2012-2016. The results of these efforts show that the disease is in a pre-elimination phase. Despite a clear decline of malaria several aspects of its epidemiology should be clarified including the identification of endemic areas. Methods: Monthly cases, as reported by the “Programme National de lutte Contre le paludisme” (PNLP) from 2010 to 2014, were geo-referenced in each island at the sanitary district level. The incidence of malaria by district was calculated using population data from the National Census. We completed the spatial database with data on environmental and social factors including meteorology, physical geography, land use (analyzed by remote sensing of SPOT 5 satellite images), population characteristics, and health care facilities. We performed statistical analyzes to show the relationships between the variables and the prevalence of malaria. Results: The mapping of malaria incidence between 2010 and 2014 shows its heterogeneity among the 17 sanitary districts. Five districts (Hambou, Centre, Fomboni, Mutsamudu and Pomoni) reveal a high endemicity. Also we have highlighted the spatial relationships between malaria incidences and environmental and socio-demographic variables. Conclusion: This work is the first spatial analysis of the epidemiology of malaria in Comoros. It contributes to a better understanding of the spatial dynamics of malaria to help the Ministry of Health to eradicate malaria by 2016.