Predators can impact ecosystems through consumptive or risk effects on prey. Physiologically, risk effects can be mediated by energetic mechanisms or stress responses. The predation-stress hypothesis predicts that risk induces stress in prey, which can affect survival and reproduction. However, empirical support for this hypothesis is both mixed and limited, and the conditions that cause predation risk to induce stress responses in some cases, but not others, remain unclear. Unusually clear-cut variation in exposure of Cape fur seals (Arctocephalus pusillus pusillus) to predation risk from white sharks (Carcharodon carcharias) in the waters of Southwestern Africa provides an opportunity to test the predation-stress hypothesis in the wild. Here, we measured fecal glucocorticoid concentrations (fGCM) from Cape fur seals at six discrete islands colonies exposed to spatiotemporal variation in predation risk from white sharks over a period of three years. We found highly elevated fGCM concentrations in seals at colonies exposed to high levels of unpredictable and relatively uncontrollable risk of shark attack, but not at colonies where seals were either not exposed to shark predation or could proactively mitigate their risk through antipredatory behavior. Differences in measured fGCM levels were consistent with patterns of risk at the site and seasonal level, for both seal adults and juveniles. Seal fGCM levels were not correlated with colony population size, density, and geographic location. Investigation at a high risk site (False Bay) also revealed strong correlations between fGCM levels and temporal variation in shark attack rates, but not with shark relative abundance. Our results suggest that predation risk will induce a stress response when risk cannot be predicted and/or proactively mitigated by behavioral responses.