Arsenic contamination of groundwater has been identified in Cambodia, where some 100,000 family-based wells are used for drinking water needs. We conducted a comprehensive groundwater survey in the Mekong River floodplain, comprising an area of 3700 km(2) (131 samples, 30 parameters). Seasonal fluctuations were also studied. Arsenic ranged from 1 to 1340 microg L(-1) (average 163 microg L(-1)), with 48% exceeding 10 microg L(-1). Elevated manganese levels (57% >0.4 mg L(-1)) are posing an additional health threat to the 1.2 million people living in this area. With 350 people km(-2) potentially exposed to chronic arsenic poisoning, the magnitude is similar to that of Bangladesh (200 km(-2)). Elevated arsenic levels are sharply restricted to the Bassac and Mekong River banks and the alluvium braided by these rivers (Kandal Province). Arsenic in this province averaged 233 microg L(-1) (median 100 microg L(-1)), while concentrations to the west and east of the rivers were <10 microg L(-1). Arsenic release from Holocene sediments between the rivers is most likely caused by reductive dissolution of metal oxides. Regions exhibiting low and elevated arsenic levels are co-incident with the present low relief topography featuring gently increasing elevation to the west and east of a shallow valley-understood as a relict of pre-Holocene topography. The full georeferenced database of groundwater analysis is provided as Supporting Information.