We previously showed that combined treatment with allopurinol plus verapamil had a salutary effect on tissue necrosis during 24-h permanent coronary occlusion. The present study was undertaken to determine whether cardioprotection with allopurinol plus verapamil as compared with either allopurinol or verapamil treatment alone could be sustained in dog hearts during 48-h permanent coronary occlusion. In 46 dogs, coronary occlusion was induced using a closed-chest embolization procedure. Four groups were studied: (a) untreated controls, (b) dogs receiving allopurinol, (c) dogs receiving verapamil, and (d) dogs receiving allopurinol plus verapamil. Tissue necrosis was evaluated using triphenyltetrazolium staining and was related to two major baseline predictors of infarct size: anatomic risk zone size and coronary collateral flow. In untreated controls, the ratio of infarct to risk zone was inversely related to coronary collateral flow; analysis of covariance (ANCOVA) indicated that treatment with allopurinol or verapamil alone and combined allopurinol plus verapamil shifted this relationship downward. In conclusion, combined treatment with allopurinol plus verapamil did not afford additional limitation of tissue necrosis as compared with either allopurinol or verapamil treatment alone; however, considerable and statistically significant limitation of tissue necrosis was observed even during 48-h permanent coronary occlusion without reperfusion.