To ascertain prognostic factors associated with fatal outcomes in severe leptospirosis, a retrospective case-control study was done using population-based surveillance data. Centralized death certificate reporting of leptospirosis mortality was combined with details of patients' hospitalizations, which were obtained from hospitals representing all sectors of São Paulo city. Among identified leptospirosis cases, 89 lethal cases and 281 survivor cases were analyzed. Predictors of death included age>40 years, development of oliguria, platelet count<70,000/microL, creatinine>3 mg/dL, and pulmonary involvement. The latter was the strongest risk factor with an estimated odds ratio of 6.0 (95% confidence interval: 3.0-12.0). Serologic findings with highest titer against Leptospira interrogans serovar Copenhageni did not show significant differences between survivors and non-survivors. Lung involvement was an important predictor of death in leptospirosis in São Paulo, of relevance in leptospirosis-endemic regions where this complication is common.