The efflux of hypoxanthine, xanthine and uric acid into cortical superfusates was studied with the cortical cup technique in the rat. Twenty minutes of four vessel occlusion followed by reperfusion results in a massive increase in the efflux of these purine metabolites. Amflutizole, 10 microM administered topically into the cortical cups, enhanced the ischemia-evoked release of hypoxanthine while it suppressed xanthine formation. Uric acid levels were not affected. Amflutizole also eliminated the ischemia/reperfusion-evoked generation of free radical adducts of alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN) detected by electron spin resonance. These results are consistent with a block of xanthine oxidase by amflutizole and support the involvement of xanthine oxidase in free radical mediated tissue damage following ischemia/reperfusion.