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Background: Brazil has the second highest case count of Hansen's disease (leprosy, HD), but factors contributing to transmission in highly endemic areas of the country remain unclear. Recent studies have shown associations of helminth infection and leprosy, supporting a biological plausibility for increased leprosy transmission in areas with helminths. However, spatial analyses of the overlap of these infections are limited. Therefore, we aimed to spatially analyze these two diseases in a co-endemic area of Minas Gerais, Brazil, in order to identify potential epidemiologic associations. Methods: An ecological study using public health surveillance records and census data was conducted to investigate whether the occurrence of HD -and specifically multibacillary (MB) disease- was associated with the presence of schistosomiasis in a community of 41 municipalities in eastern Minas Gerais, Brazil from 2011 to 2015. Multivariate logistic regression and spatial cluster analyses using geographic information systems (GIS) were performed. Results: The average annual incidence of HD in the study area was 35.3 per 100,000 while Schistosoma mansoni average annual incidence was 26 per 100,000. Both HD and schistosomiasis were spatially distributed showing significant clustering across the study area. Schistosomiasis was present in 10.4% of the tracts with HD and thirteen high-high clusters of local bivariate autocorrelation for HD and schistosomiasis cases were identified. A multivariate non-spatial analysis found that census tracts with MB disease were more likely to have schistosomiasis when adjusted for population density, household density, and household income (aOR = 1.7, 95% CI 1.0, 2.7). This remained significant when accounting for spatial correlation (aOR = 1.1, 95% CI (1.0, 1.2)). Conclusion: We found clustering of both HD and schistosomiasis in this area with some statistically significant overlap of multibacillary HD with S. mansoni infection. Not only did we provide an effective approach to study the epidemiology of two endemic neglected tropical diseases with geographic spatial analyses, we highlight the need for further clinical and translational studies to study the potential epidemiologic associations uncovered. Author summary: As cases of Hansen's disease decrease globally, areas with high endemicity still struggle to control infections. In Brazil, which has the second highest burden of disease globally, new measures are necessary to reach elimination. Not only are geographic information systems (GIS) important tools to describe the heterogeneity of infectious diseases on a finer scale, it can also be used to study the overlap of two different endemic infections. Due to several studies showing potential associations between helminth infection and Hansen's disease, this study explores a co-endemic helminth infection (Schistosoma mansoni) as a potential factor in the continued transmission of leprosy. Our objective was to spatially analyze these two diseases and identify potential epidemiologic associations in 41 municipalities in the state of Minas Gerais, Brazil. Our study found the risk of MB disease was over 1.5 time greater in census tracts with reported schistosomiasis than in tracts without, adjusted for socioeconomic and environmental factors. We also identified several clusters of schistosomiasis and MB disease. While these findings can provide immediate data for control programs to utilize, it also calls for further studies on the interplay of co-infections in the manifestations of HD that may shed light on ongoing transmission in highly endemic areas. [ABSTRACT FROM AUTHOR]