Introduction:Leptospirosis is an infectious disease that affects more than 5,000 people per year in Brazil. The Federal District (FD) lacks epidemiological studies of human leptospirosis and presents concerning rates of this disease, especially considering its lethality. Methods: Seventy-nine autochthonous human cases of leptospirosis between 2011 and 2015 were analyzed, with the probable infection location serving as a basis for the collection and analysis of the environmental and epidemiological variables. Results: The incidence of the disease ranged from 0.68-13.39 per 100,000 inhabitants in 21 of the 31 administrative regions that compose the FD. The local profi le of human leptospirosis was predominantly associated with urban areas during the rainy season, population access to the sewage network, the treated water network, and the public garbage collection service. The vast majority of cases had a strong association with synanthropic rodents at the infection sites. Conclusions: In order to prevent and control potentially lethal human leptospirosis infection, the eco-epidemiological characterization of this disease is a valuable tool for public policies of prevention, control, and surveillance. In addition to population awareness, the systematized control of synanthropic rodents could be the main health action to reduce the incidence of this disease in the FD.