Flow-mediated dilation (FMD) is strongly dependent on arterial size, but the reasons for this phenomenon are poorly understood. We have previously shown that FMD is greater in small brachial arteries because the shear stress stimulus is greater in small brachial arteries. However, it is unclear why the shear stimulus is greater in small arteries. Furthermore, this relationship has not been investigated in other, differently sized arterial beds. Postischemic systolic shear stress and resulting FMD were evaluated in the brachial and femoral arteries of 24 young, healthy adults using phase-contrast magnetic resonance imaging. Arterial shear and radius were calculated from the velocity profile via a best-fit parabola before and after occlusion. Summing the velocity pixels provided hyperemic systolic flow. FMD was proportional to hyperemic shear in the brachial and femoral arteries (P < 0.0001, r = 0.60). Hyperemic systolic flow was proportional to radius2 (P < 0.0001, r = 0.93). Applying this relationship to the Poiseuille equation (shear is proportional to flow/radius3) shows that hyperemic shear is proportional to radius2/radius3 and, therefore, explains why hyperemic shear is proportional to 1/radius. We conclude that FMD is proportional to hyperemic systolic shear stress in both the brachial and the femoral arteries. The hyperemic shear stimulus for FMD is greater in small arteries due to the dependence of postischemic systolic flow on radius squared. Therefore, greater FMD in small arteries does not necessarily reflect better conduit artery endothelial function. Evaluating the shear stimulus using phase-contrast magnetic resonance imaging enhances the understanding of mechanisms underlying FMD.