To assess the potential role of platelet inhibitory agents in the treatment of myocardial infarction, the effect on infarct size of two platelet inhibitors, sulfinpyrazone and naproxen, was evaluated. In addition to platelet inhibition, sulfinpyrazone increases epicardial collateral flow and naproxen has lysosomal-stabilizing activity. Thirty-eight open chest dogs were given intravenously sulfinpyrazone (30 mg/kg, n = 11), naproxen (30 mg/kg, n = 14) or saline solution (n = 13) 10 minutes before and 3 and 6 hours after ligation of the mid left anterior descending coronary artery. Drug doses were sufficient to inhibit adenosine diphosphate-induced platelet aggregation. The dogs were killed 72 hours after occlusion. Myocardium at risk of infarction-that is, the area supplied by the occluded artery (anatomic risk area)-was identified by simultaneous perfusion of the aortic root with Evans blue and of the coronary artery distal to the occlusion with clear saline solution. Hearts were sliced horizontally and stained with triphenyl-tetrazolium-chloride. The infarcted area and anatomic risk area were measured with videoplanimetry. The percent of left ventricle infarcted was not significantly different among the control, sulfinpyrazone and naproxen groups (28 ± 2, 30 ± 1, 28 ± 2 percent, respectively) nor was percent of anatomic risk area infarcted significantly different (75 ± 3, 79 ± 3, 75 ± 3 percent, respectively). Thus, neither sulfinpyrazone nor naproxen in platelet inhibitory doses altered infarct size. These results indicate that neither inhibitory effects on platelet function and prostaglandin synthesis nor associated lysosomal-stabilizing properties identify agents with consistent infarct-sparing action.