BACKGROUND Leptospirosis is an endemic disease in Brazil that can become an epidemic during the rainy season resulting from floods in areas susceptible to natural disasters. These areas are widespread in Santa Catarina, particularly in the coastal region. Therefore, the objective of this study was to identify environmental, climatic, and demographic factors associated with the incidence of leptospirosis in the municipalities of Santa Catarina from 2001 to 2015, taking into account possible spatial dependence. METHODS This was an ecological study aggregated by municipality. To evaluate the association between the incidence of leptospirosis and the factors under study (temperature, altitude, occurrence of natural disasters, etc.) while taking into account spatial dependence, linear regression models and models with global spatial error were used. RESULTS Lower altitudes, higher temperatures, and areas of natural disaster risk in the municipality contributed the most to explaining the variability in the incidence rate. After taking spatial dependence into account, only the minimum altitude variable remained significant. The regions of lower altitude, where the highest rates of leptospirosis were recorded, corresponded to the eastern portion of the state near the coastal region, where floods, urban floods, and overflows are common occurrences. No associations were found concerning demographic factors. CONCLUSIONS The incidence of leptospirosis in Santa Catarina was associated with environmental factors, particularly low altitude, even when considering the spatial dependence structure present in the data. The spatial error model allowed for adequate modeling of spatial autocorrelation.