Deep aquifers in South and Southeast Asia are increasingly exploited as presumed sources of pathogen- and arsenic-free water, although little is known of the processes that may compromise their long-term viability. We analyze a large area (>1,000 km(2)) of the Mekong Delta, Vietnam, in which arsenic is found pervasively in deep, Pliocene-Miocene-age aquifers, where nearly 900 wells at depths of 200-500 m are contaminated. There, intensive groundwater extraction is causing land subsidence of up to 3 cm/y as measured using satellite-based radar images from 2007 to 2010 and consistent with transient 3D aquifer simulations showing similar subsidence rates and total subsidence of up to 27 cm since 1988. We propose a previously unrecognized mechanism in which deep groundwater extraction is causing interbedded clays to compact and expel water containing dissolved arsenic or arsenic-mobilizing solutes (e.g., dissolved organic carbon and competing ions) to deep aquifers over decades. The implication for the broader Mekong Delta region, and potentially others like it across Asia, is that deep, untreated groundwater will not necessarily remain a safe source of drinking water.