The number of perfused capillaries in skeletal muscle varies with muscle activation. With increasing activation, muscle fibers are recruited as motor units consisting of widely dispersed fibers, whereas capillaries are recruited as groups called microvascular units (MVUs) that supply several adjacent fibers. In this study, a theoretical model was used to examine the consequences of this spatial mismatch between the functional units of muscle activation and capillary perfusion. Diffusive oxygen transport was simulated in cross sections of skeletal muscle, including several MVUs and fibers from several motor units. Four alternative hypothetical mechanisms controlling capillary perfusion were considered. First, all capillaries adjacent to active fibers are perfused. Second, all MVUs containing capillaries adjacent to active fibers are perfused. Third, each MVU is perfused whenever oxygen levels at its feed arteriole fall below a threshold value. Fourth, each MVU is perfused whenever the average oxygen level at its capillaries falls below a threshold value. For each mechanism, the dependence of the fraction of perfused capillaries on the level of muscle activation was predicted. Comparison of the results led to the following conclusions. Control of perfusion by MVUs increases the fraction of perfused capillaries relative to control by individual capillaries. Control by arteriolar oxygen sensing leads to poor control of tissue oxygenation at high levels of muscle activation. Control of MVU perfusion by capillary oxygen sensing permits adequate tissue oxygenation over the full range of activation without resulting in perfusion of all MVUs containing capillaries adjacent to active fibers.