Computer simulation of blood flow and O2 consumption (QO2) of leg muscles and of blood flow through other vascular compartments was made to estimate the potential effects of circulatory adjustments to moderate leg exercise on pulmonary O2 uptake (VO2) kinetics in humans. The model revealed a biphasic rise in pulmonary VO2 after the onset of constant-load exercise. The length of the first phase represented a circulatory transit time from the contracting muscles to the lung. The duration and magnitude of rise in VO2 during phase 1 were determined solely by the rate of rise in venous return and by the venous volume separating the muscle from the lung gas exchange sites. The second phase of VO2 represented increased muscle metabolism (QO2) of exercise. With the use of a single-exponential model for muscle QO2 and physiological estimates of other model parameters, phase 2 VO2 could be well described as a first-order exponential whose time constant was within 2 s of that for muscle QO2. The use of unphysiological estimates for certain parameters led to responses for VO2 during phase 2 that were qualitatively different from QO2. It is concluded that 1) the normal response of VO2 in humans to step increases in muscle work contains two components or phases, the first determined by cardiovascular phenomena and the second primarily reflecting muscle metabolism and 2) the kinetics of VO2 during phase 2 can be used to estimate the kinetics of muscle QO2. The simulation results are consistent with previously published profiles of VO2 kinetics for square-wave transients.