Background The role of ribavirin for treatment of severe acute or chronic hepatitis E virus (HEV) infection is not well defined. Aims To investigate the applicability and efficacy of ribavirin therapy in acute and chronic HEV infections within a large single-centre cohort. Materials & Methods Clinical courses of forty-four German HEV-infected individuals were analysed. Results In a prospective case series, we observed spontaneous recovery from acute symptomatic HEV-infection in 10/11 immunocompetent individuals. Ribavirin therapy was initiated in one patient with severe acute HEV-genotype-1e infection who rapidly improved liver function and cleared HEV. Of 15 organ transplant recipients with prolonged HEV viraemia, reduction in immunosuppression led to HEV-clearance in three patients, while ribavirin therapy was initiated in 11 subjects. A rapid response with undetectable HEV-RNA occurred in nine subjects. One patient died after experiencing a virological breakthrough associated with ribavirin dose reduction because of severe anaemia. Discussion Ribavirin is a safe treatment option for HEV infections. However, the optimal dose of ribavirin for the treatment of chronic hepatitis E remains to be determined as treatment failure may occur.