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Ectotherms often attain smaller body sizes when they develop at higher temperatures. This phenomenon, known as the temperature-size rule, has important consequences for global fisheries, whereby ocean warming is predicted to result in smaller fish and reduced biomass. However, the generality of this phenomenon and the mechanisms that drive it in natural populations remain unresolved. In this study, we document the maximal size of 74 fish species along a steep temperature gradient in the Mediterranean Sea and find strong support for the temperature-size rule. Importantly, we additionally find that size reduction in active fish species is dramatically larger than for more sedentary species. As the temperature dependence of oxygen consumption depends on activity levels, these findings are consistent with the hypothesis that oxygen is a limiting factor shaping the temperature-size rule in fishes. These results suggest that ocean warming will result in a sharp, but uneven, reduction in fish size that will cause major shifts in size-dependent interactions. Moreover, warming will have major implications for fisheries as the main species targeted for harvesting will show the most substantial declines in biomass.