Nitric oxide (NO), originally identified as the mediator of endothelial‐dependent relaxation of vascular smooth muscle, is now known to also have cytotoxic effects under certain conditions. Thus, we have investigated the effects of inhibition of NO synthesis on ischemia/reperfusion injury in the rabbit rectus femoris muscle. Three and a half hours of ischemia and 24 hours of reperfusion resulted in a 56% loss of viability. In muscles receiving an infusion of the nitric oxide synthase inhibitor, L‐NIO (30 μM), the loss of viability was reduced to 15%. Post‐ischemic blood flow was increased in muscles receiving a saline infusion, whereas there was a marked decrease in blood flow for at least the first 60 minutes of reperfusion in muscles treated with L‐NIO (30 μM). The increase in myeloperoxidase levels (indicative of neutrophil accumulation) following 24 hours of reperfusion was attenuated with L‐NIO infusion by approximately 50% and the reperfusion‐induced edema was also attenuated in L‐NIO treated muscle. These findings suggest that endogenous NO production during ischemia/reperfusion injury may be deleterious to muscle survival. © 1994 Wiley‐Liss, Inc.