Schistosomiasis found in communities along the Mekong River in Cambodia and Lao People's Democratic Republic (Lao PDR) is caused by the blood fluke Schistosoma mekongi. Early observations on patients in 1957 revealed severe intestinal and hepatosplenic disease. High mortality rates and widespread disease were reported from the provinces of northern Cambodia (Stung Treng and Kratié) and southern Lao PDR (Champasack) in the early 1970s and 1990s. Control programmes built around mass drug administration, with praziquantel, and combined with information and education campaigns, were carried out. In Cambodia, such programmes were started in 1995 in the endemic provinces and sustained until today; these efforts resolved the public health problem of schistosomiasis mekongi and led to a significant reduction in transmission. In Lao PDR, the interventions started in the late 1980s, but suffered several interruptions which permitted transmission to resume. Today, a number of small foci continue to show substantial prevalence rates. The snail intermediate host, Neotricula aperta, is present in the Mekong River and some of its tributaries. There is evidence that the snail might not yet have reached its full geographical distribution emphasising the need to sustain vigilance. New infections with S. mekongi occur in the endemic population and travellers alike. Comprehensive guidelines for the elimination of S. mekongi and bilateral efforts between Cambodia and Lao PDR are required.