It it commonly believed that vagally mediated bradycardia predisposes to ventricular fibrillation (VF) during acute myocardial ischemia. Recent experimental studies, however, have shown that bradycardia and vagal stimulation independently raise the threshold for electrically induced VF in the ischemic canine heart. To determine the influence of vagal stimulation on the spontaneous development of VF occurring during acute myocardial ischemia, open chest dogs with acute coronary occlusion were observed with and without electrical vagal stimulation. When heart rate was allowed to fall, mean time to VF was 14.7 ± 2.1 min (SE) in the control dogs (heart rate about 180/min), 23.4 ± 1.9 (P < 0.01) in the dogs with low intensity vagal stimulation (heart rate about 100/min), and 28.6 ± 0.9 (P < 0.001) in dogs with high intensity vagal stimulation (heart rate about 60/min). Only 10% of the control animals survived after 30 min of occlusion compared with 40% (NS) of the dogs with low intensity vagal stimulation and 71% (P < 0.05) of the dogs with high intensity vagal stimulation. Thus, vagal stimulation and bradycardia were associated with a postponement or prevention of VF. In a second series of animals with heart rate maintained constant by right ventricular pacing, vagal stimulation continued to exert a protective effect against the development of VF. Time to VF was increased from 11.0 ± 2.0 min in control animals to 22.6 ± 2.5 in dogs with vagal stimulation (P < 0.005), and percent survival was enhanced (12% in control animals versus 57% in the vagally stimulated group, P < 0.02). Similar results were observed in a third series of dogs in which electrical stimulation was applied to the peripheral ends of the cut cervical vagi. It is concluded that vagal stimulation, with or without accompanying bradycardia, reduces the incidence of spontaneous VF in experimental coronary occlusion. Thus, enhanced vagal tone might act to reduce, rather than increase, the risk of arrhythmic death occurring during acute myocardial ischemia in man.