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Environmental stress gradients can affect species distributions and interspecific interactions. Because environmental stress depends on both intensity and duration, understanding the consequences of stress requires experiments that simultaneously manipulate both dimensions. In Apalachicola Bay, Florida (U.S.A.) the southern oyster drill (Stramonita haemastoma) is a major predator of the eastern oyster (Crassostrea virginica). Drill predation appears to be salinity-dependent: in a recent field study, predation rates were positively correlated with salinity. Salinity in the bay is typically high (> 20) during the dry summer months, conditions that favor both oysters and the drill. However, periodic freshets can dramatically reduce salinity, which inhibits (or kills) drills, but not oysters. In this study, we used field measurements of salinity and drill densities to inform mesocosm experiments. We investigated the specific combinations of intensity and duration of low-salinity stress that inhibit drill predation. In these experiments, more intense salinity reductions reduced feeding both during and after the low-salinity stress event. During the event, longer durations (15 d) were necessary for mild salinity reductions (-5) to reduce the feeding rate by the same amount as a short (5 d) exposure of more intense (-10 or -15) salinity reduction. Both conditions may create a predation refuge for oysters, consistent with field observations. Given that the recent collapse of the Apalachicola Bay oyster population was preceded by several years without low-salinity events to inhibit predation, our results provide a mechanism by which a predator may have contributed to the loss of a historically productive and sustainable fishery.