Cardiac arrhythmias during ischemia/reperfusion are believed to be related to free radicals generated in the heart especially during the period of reperfusion. Since melatonin functions as a free radical scavenger and antioxidant, the ability of this molecule to influence cardiac arrhythmias was investigated. The pineal secretory product, melatonin, reduced the incidence and severity of arrhythmias induced by ischemia/reperfusion due to ligation of the anterior descending coronary artery in the isolated rat heart. Melatonin was either infused during both the ischemia and reperfusion periods or only late in the ischemia period and throughout reperfusion. The percentage of hearts that developed cardiac arrhythmias during reperfusion as indicated by the incidence of premature ventricular contraction (PVC) and ventricular fibrillation (VF) were recorded. Melatonin either infused during both the ischemia and reperfusion periods or during essentially the period of reperfusion greatly reduced PVC and VF due to occlusion and reopening the anterior descending coronary artery. Presumably melatonin's beneficial effect in reducing cardiac arrhythmias was due in part to its free radical scavenging activity, which is greatly assisted by the rapidity with which it is taken up into cells. Previous studies have shown that vitamin C is effective in reducing the severity of cardiac arrhythmias induced by ischemia/reperfusion; thus, we also compared the efficacy of melatonin with this well-known antioxidant. Melatonin was more potent than vitamin C in protecting against arrhythmias induced by ischemia/reperfusion. Besides melatonin's function as a broad spectrum free radical scavenger, melatonin may have also reduced cardiac arrhythmias due to its regulation of intracellular calcium levels, i.e., by preventing calcium overloading, or due to its ability to suppress sympathetic nerve function and reduce adrenergic receptor function in the myocardium. Additional studies into the mechanisms of melatonin's action in reducing cardiac arrhythmias due to ischemia/reperfusion or other causes are warranted because of the possible application of this information to humans with heart disease.