Hepatitis E infection is usually a self-limiting disease. In industrialized countries, sporadic cases of acute hepatitis E virus (HEV) infections have been described; their number seems to be increasing in European countries. We report the first human case of autochthonous acute hepatitis E confirmed in Portugal. Patients with acute non-A-C hepatitis should be tested for HEV in Portugal and hepatitis E infection should be considered in the differential diagnosis of unexplained hepatitis cases.