Animal studies have shown that angiogenic factors can increase vascularity and improve blood pressure (BP) in an ischemic limb. Whether changes in these parameters are indicators of significant improvement in muscle function has not been demonstrated. In a rabbit model of hind limb ischemia, we measured blood flow in the extensor digitorum longus muscle (EDL) both at rest and during electrical stimulation. Ablation of the femoral artery caused significant reductions in resting and stimulated EDL blood flow. The chronic reduction in perfusion caused impairment of muscle function (p < 0.01). At 28 days after a single administration of vascular endothelial growth factor (VEGF), stimulated muscle blood flow (3 mg/kg intravenously, i.v.) and muscle function [1 mg intrarterially (i.a.) or 3 mg/kg i.v.] were significantly improved as compared with that of vehicle-treated controls. Simultaneous measurement of the hemodynamic responses in the contralateral limb and in the kidneys confirmed that the effects of VEGF were confined to the ischemic limb. The data agree with findings that angiogenic factors increase perfusion through angiogenesis. We hypothesized that neovascularization allows work-associated muscle hyperemia, resulting in a significant improvement in muscle function. Similar clinical improvements in muscle function would signify a substantial advance in the treatment of peripheral vascular disease.