OBJECTIVE: To identify risk factors for in-hospital mortality in patients treated for visceral leishmaniasis (VL) in Uganda. METHODS: Retrospective analysis of VL patients' clinical data collected for project monitoring by Medecins Sans Frontieres in Amudat, eastern Uganda. RESULTS: Between 2000 and 2005, of 3483 clinically suspect patients, 53% were confirmed with primary VL. Sixty-two per cent were children <16 years of age with a male/female ratio of 2.2. The overall case-fatality rate during pentavalent antimonial (n = 1641) or conventional amphotericin B treatment (n = 217) was 3.7%. There was no difference in the case-fatality rate between treatment groups (P > 0.20). The main risk factors for in-hospital death identified by a multivariate analysis were age <6 years and >15 years, concomitant tuberculosis or hepatopathy, and drug-related adverse events. The case-fatality rate among patients >45 years of age was strikingly high (29.0%). CONCLUSION: Subgroups of VL patients at higher risk of death during treatment with drugs currently available in Uganda were identified. Less toxic drugs should be evaluated and used in these patients.