Hepatitis E virus (HEV) is a common causative agent of acute hepatitis in many developing countries where standards of sanitation and hygiene are poor. HEV is transmitted primarily by the fecal-oral route. However, zoonotic trasmission from animal reservoirs to human by consumption of raw or undercooked meat has also been suggested. In endemic areas, HEV infection occurs as large waterborne epidemics and/or small outbreaks. Sporadic cases of HEV infection have also been reported in developed countries, where its occurrence is not always associated with travel to highly endemic areas. HEV mammalian isolates are classifi ed into four genotypes 1-4, which appear to have a specifi c host range and geographical distribution. The epidemiology of HEV in South America seems to be complex and seroprevalence in human and domestic pigs diff ers both among populations within the same countries and between countries. Additionally, HEV strains have been detected and molecularly characterized and genotype 3 is the most frequently genotype found in the region. Moreover, except for two strains isolated from autochthonous cases of acute hepatitis that occurred in Venezuela and belonged to genotype 1, all sequences detected in South America were classifi ed as within genotype 3. Our understanding of HEV epidemiology has undergone major changes in recent years and despite the fact that several attempts to shed light over the epidemiology of this infection have been carried out in South America, data about the molecular characterization of HEV isolates is still lacking and further investigation is needed. This review summarizes the current status of HEV molecular epidemiology from a regional point of view.