The geographic distribution of leptospirosis is widespread but no national surveillance program exists in Nepal to establish the incidence of leptospirosis or the disease burden. This study reports the incidence of symptomatic leptospirosis in military personnel participating in an efficacy study of a hepatitis E virus vaccine in Nepal. Among the 1566 study volunteers who completed follow-up, we evaluated 271 illnesses over 2.2 years for the presence of leptospira IgM antibodies by ELISA. Positive ELISA results were confirmed by the microscopic agglutination test. The annual incidence of disease was between 3.5 and 6.1 cases/1000. The prevalence of confirmed leptospirosis was 9% among hepatitis cases and 8% among febrile cases. The most reactive serovars were Bratislava, Autumnalis, Icterohaemorrhagiae, and Sejroe. Leptospirosis should be considered in the differential diagnosis of febrile illnesses and icteric syndromes in Nepal. Additional studies are needed to establish the broader distribution and the spectrum of disease in Nepal.