Hepatitis E virus (HEV), which is transmitted via the fecal-oral route, causes acute hepatitis that is clinically indistinguishable from other forms of acute viral hepatitis. The severity of the infection correlates with the patient’s age; during epidemics in developing countries, the mortality rate is estimated at 1% in the general population and nearly 30% among pregnant women. In industrialized countries, most cases are imported; however, genuine indigenous cases of hepatitis E have been reported in countries with high hygiene standards, including France, without any history of travel to endemic areas. While in endemic countries transmission is linked to the consumption of water or food contaminated with fecal matter, the source of contamination responsible for indigenous cases in the most developed countries is not clearly defined. The activities of the National Reference Center (NRC) for HEV, focused on expert assessment and diagnosis based on human samples sent to the NRC, are presented for the first three years of operation (2002 to 2004). (Authors’ Introduction)