Ventricular arrhythmia production in the ischemic heart is considered to be influenced by prior infarction. Although beta-ad-renergic blockade is known to have beneficial effects during acute ischemia, its anti-arrhythmic efficacy during post-infarction ischemia is not known. To explore this question, we have used a model with a relatively high incidence of ischemic arrhythmias. Mongrel dogs 2 to 3 years of age were studied intact under anesthesia. An irreversible injury of the infero-posterior myocardium was produced with an electrode catheter 1 week earlier. The arrhythmic response to acute ischemia was assessed using serial, transient 15-minute occlusions of the left-anterior descending coronary artery with a balloon catheter. During ischemia alone, the incidence of ventricular fibrillation in animals who underwent all phases of the study was 6 of 9; with atenolol (0.2 mg/kg intravenously) and ischemia, 1 of 9 (p < 0.05). To assess the role of the bradycardic response, the latter was repeated 1 week subsequently during atrial pacing at the heart rate that existed before ischemia. Fibrillation occurred in 8 of 9, a significant reversal of the therapeutic effect. To exclude the potential artifact of a fixed intervention protocol, a study was undertaken with the short-acting esmolol, in which three ischemic periods were alternated at 1-hour intervals: (A) ischemia without treatment, (B) ischemia with continuous infusion of 150 jug/kg/min esmolol, and (C) same as B except that heart rate was maintained by atrial pacing. Ventricular fibrillation occurred in 7 of 10 in period A, 1 of 10 (p < 0.03) in period B, and 8 of 10 in period C (p < 0.02). Therefore, despite the high incidence of fibrillation without treatment, beta-adrenergic blockade was effective in reducing the incidence of ventricular fibrillation during early ischemia.