1. The hypothesis that early verapamil (VP) treatment in acute myocardial ischemia can enhance the effects of subsequent reperfusion was tested in open-chest dogs submitted to 3 h of left anterior descending artery occlusion and 2 h of reperfusion. 2. Arterial pressure and heart rate were monitored continuously. The area at risk (AR) was determined by left atrial injection of 99technetium-labeled microspheres soon after occlusion. The area of necrosis (AN) was identified histologically with triphenyl tetrazolium chloride and calculated as percent of AR. Myocardial preservation is reported as percent of AR spared from necrosis (AR-AN) x 100/AR. 3. Fourteen dogs received 0.2 mg VP, iv, 15 min after occlusion and 9 untreated dogs served as controls. Verapamil significantly reduced heart rate but did not affect blood pressure or the pressure-heart rate product. 4. Myocardial preservation was significantly greater in verapamil-treated dogs than in control animals (51 +/- 20 vs 31 +/- 19%, mean +/- SD). However, area at risk (%) in the left ventricle was not significantly different in treated and control animals (31 +/- 12 vs 32 +/- 4%). 5. These data indicate that verapamil protects the ischemic myocardium in this occlusion/reperfusion model and that the mechanism of protection is probably related to a non-hemodynamic, metabolic activity of verapamil.