Coronary occlusion in the dog results in irreversible myocardial cell injury which develops first in subendocardial areas of severe ischemica and subsequently spreads into mid and subepicardial areas of moderate ischemia. The effect of propranolol on this progression of ischemic injury was evaluated. Three groups of dogs were studied: 1) untreated, 2) treated with propranolol before and throughout coronary ligation, and 3) treated with propranolol beginning three hours after ligation. Dogs were sacrificed 24 hours after coronary ligation and necrosis was quantitated from histologic sections of transmural slices through the posterior papillary muscle. Propranolol reduced infarct size by preventing necrosis in peripheral (subepicardial) areas of moderately ischemic myocardium. Pretreatment with propranolol reduced necrosis from 85 +/- 3% (untreated) to 52 +/- 4% (P less than 0.05). Delayed propranolol therapy was about half as effective as pre-treatment and reduced necrosis to 71 +/- 3% (P less than 0.05). Propranolol also limited microvascular injury so that perfusion defects, detected with the dye thioflavin S, were smaller in treated dogs.