The incidence of free flap transplantation failure is only 3% to 5%, yet still occurs in cases in which the flap suffers prolonged ischemia. The purpose of the current study was to determine the effects of vascular endothelial growth factor (VEGF)--a potent angiogenic agent with a suspected role in the protection of endothelium--on flap survival in a model of ischemia-reperfusion injury. The model chosen was the rat gracilis muscle flap. A total of 36 adult male Sprague-Dawley rats were divided into three groups (N = 12). One experimental group received VEGF treatment and the other received heparin. A third group was treated with saline and served as the control. The gracilis muscle flap was dissected and isolated based on a vascular pedicle originating at the femoral vessels. Following 3.75 hours of ischemia, induced by clamping the femoral vessels, either VEGF, heparin, or saline was infused directly into the pedicle of the flap via a cannula. The flaps were evaluated both grossly and histologically after 72 hours of reperfusion. Eleven of the 12 flaps from the VEGF group survived, whereas the survival rate was 6 of 12 and 5 of 12 flaps for the heparin- and saline-treated groups respectively. Flap survival was significantly greater in the VEGF-treated group compared with the heparin- and saline-treated groups (p < 0.025, p < 0.01 respectively). Furthermore, there was no significant difference between the heparin and saline groups. These results indicate that VEGF plays a role in reducing the damage that occurs in ischemia-reperfusion injury, and that the use of VEGF holds promise as a potential therapy for increasing flap survival.