The role of oxygen-derived free radicals in reperfusion arrhythmias was investigated in open-chest anesthetized dogs. The left anterior descending coronary artery was cannulated and perfused by an arterial bypass shunt. Ischemia was produced for 15 min by shunt occlusion and retrograde diversion of collateral blood flow. Dogs (n = 12) were treated with saline, N-(2-mercaptopropionyl)glycine (50 mg/kg), deferoxamine (10 mg/kg), superoxide dismutase (15,000 U/kg) plus catalase (55,000 U/kg), or dimethylthiourea (500 mg/kg). All agents were infused intravenously for 1 h starting 30 min before occlusion and continuing for 5 min of reperfusion. There were no differences in mean arterial blood pressure, heart rate, antegrade coronary flow, retrograde coronary flow, or size of the risk region among the five treatment groups. None of the dogs developed ventricular fibrillation during occlusion, whereas 88% of the 60 dogs fibrillated upon reperfusion. The antioxidant interventions did not alter the incidence of reperfusion-induced ventricular fibrillation compared with the saline-treated controls. The results suggest that free radicals do not play a role in lethal canine reperfusion arrhythmias.