The ecology of hepatitis E virus (HEV) transmission in South-East Asia was assessed from a review of 6 published and 3 unpublished NAMRU-2 reports of hepatitis outbreak investigations, cross-sectional prevalence studies, and hospital-based case-control studies. Findings from Indonesia and Viet Nam show epidemic foci centred in jungle, riverine environments. In contrast, few cases of acute, clinical hepatitis from cities in Indonesia, Viet Nam and Laos could be attributed to HEV. When communities in Indonesia were grouped into areas of low (< 40%), medium (40-60%), and high (> 60%) prevalence of anti-HEV antibodies, uses of river water for drinking and cooking, personal washing, and human excreta disposal were all significantly associated with high prevalence of infection. Conversely, boiling of river drinking water was negatively associated with higher prevalence (P < 0.01). The protective value of boiling river water was also shown in sporadic HEV transmission in Indonesia and in epidemic and sporadic spread in Viet Nam. Evidence from Indonesia indicated that the decreased dilution of HEV in river water due to unusually dry weather contributed to risk of epidemic HEV transmission. But river flooding conditions and contamination added to the risk of HEV infection in Viet Nam. These findings attest to a unique combination of ecological and environmental conditions predisposing to epidemic HEV spread in South-East Asia.