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Between March and October 2000, 157 suspected cases of leptospirosis hospitalized with complications of Weil's syndrome and a mortality of 8% were identified in Salvador, Brazil. We conducted a population-based case-control study to identify risk factors for acquisition of leptospirosis in neighborhoods with high endemicity during the rainy season-associated urban epidemic. Sixty-six (65%) of 101 laboratory-confirmed cases and 125 age and sex-matched healthy neighborhood controls were interviewed. Residence in proximity to an open sewer (matched odds ratio [OR] = 5.15, 95% confidence interval [CI] = 1.80-14.74), peri-domiciliary sighting of rats (OR = 4.49, 95% CI = 1.57-12.83), sighting groups of five or more rats (OR = 3.90, 95% CI = 1.35-11.27), and workplace exposure to contaminated environmental sources (OR = 3.71, 95% CI = 1.35-10.17) were found to be independent risk factors for acquiring disease. Some of these risk factors are amenable to focused interventions, which include provision of closed drainage systems for sewage and reduction of rodent populations in the peri-domicilary environment. Environmental control of transmission may help to greatly reduce the incidence of severe leptospirosis.