Pressure is a key control on the progress of metamorphic reactions. When fluids are present in rocks, the fluid pressure is commonly different to the load supported by the solid framework. Here, we show experimentally that, when the two pressures are varied independently, fluid pressure exerts the dominant control on reaction rate, even when the rock is compacting. We present 35 experiments on gypsum dehydration with independently controlled confining pressure, pore fluid pressure and temperature. Results show that a pore fluid pressure decrease at constant confining pressure has a strong effect on the average rate of the reaction. A decrease in confining pressure at constant pore fluid pressure has relatively little effect. Our results have implications for reaction kinetics: even though the product phase is supporting more and more load as reaction proceeds, that load does not appear to exert a chemical effect. On the large scale, our results imply that changes in fluid pressure will drive or stop the progress of metamorphic reactions. When estimating depth at which a metamorphic devolatilization reaction occurs, knowledge of the pore fluid pressure may be necessary rather than commonly used lithostatic pressure. This is relevant for basin diagenesis, mineralization in hydrothermal systems and chemical evolution after pore fluid pressure is perturbed by earthquakes.