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The highly populated floodplains of the Bengal Delta have a long history of endemic and epidemic cholera outbreaks, both coastal and inland. Previous studies have not addressed the spatio-temporal dynamics of population vulnerability related to the influence of underlying large-scale processes. We analyzed spatial and temporal variability of cholera incidence across six surveillance sites in the Bengal Delta and their association with regional hydroclimatic and environmental drivers. More specifically, we use salinity and flood inundation modeling across the vulnerable districts of Bangladesh to test earlier proposed hypotheses on the role of these environmental variables. Our results show strong influence of seasonal and interannual variability in estuarine salinity on spring outbreaks and inland flooding on fall outbreaks. A large segment of the population in the Bengal Delta floodplains remain vulnerable to these biannual cholera transmission mechanisms that provide ecologic and environmental conditions for outbreaks over large geographic regions.