We have assessed whether the xanthine oxidase inhibitor, allopurinol, can afford maximal protection against the formation of reperfusion-induced arrhythmias or whether the addition of free radical scavengers and anti-oxidants can increase this protection. Using an anesthetized rat preparation with transient coronary artery occlusion, we have compared the ability of allopurinol pretreatment alone to that of a combination therapy of allopurinol, superoxide dismutase, and catalase to reduce the incidence of reperfusioninduced arrhythmias. While both regimes reduced the incidence of reperfusion-induced ventrieular fibrillation (from 87% to 40%, p < 0.05 by allopurinol alone; and to 13%, p < 0.01 by combination therapy), and both treatments eliminated mortality, only combination therapy reduced the incidence of reperfusion-induced ventricular tachycardia (from 87% to 40%, p < 0.05). Furthermore, using an arrhythmia score analysis, combination therapy was shown to offer significantly greater protection than allopurinol alone. This additional protection afforded by combination therapy was also demonstrated by significant decreases in logl0 duration of fibrillation and lOgl0 number of premature ventricular complexes compared with allopurinol alone. Both allopurinol and combination therapy also significantly delayed the ischemiainduced increases in ST segment elevation, although there was no difference between the two drug-treated groups. We conclude from these results that allopurinol does not offer maximal protection against reperfusion-induced arrhythmias and that the addition of more general anti-oxidant therapy can increase this protection.