The effect of nitroglycerin on vulnerability to ventricular fibrillation was examined in 44 chloralose-anesthetized dogs. In 19 animals ventricular fibrillation threshold was measured before and during a 10 minute period of occlusion of the left anterior descending coronary artery followed by abrupt release of occlusion. Fibrillation threshold was determined using the single stimulus and train of stimuli methods. The influence of nitroglycerin on vulnerability was assessed with and without prevention of the drug's hypotensive effect by intravenous injection of phenylephrine. In the nonischemic myocardium, infusion of nitroglycerin alone or in combination with phenylephrine did not alter the ventricular fibrillation threshold. However, during both coronary occlusion and reperfusion, administration of nitroglycerin alone afforded partial protection against vulnerability to ventricular fibrillation. Nearly complete protection was imparted by combined administration of nitroglycerin and phenylephrine. The incidence of spontaneous ventricular fibrillation during reperfusion was significantly reduced by combined administration of nitroglycerin and phenylephrine. It is concluded that infusion of nitroglycerin decreases susceptibility to ventricular fibrillation during both acute myocardial ischemia and reperfusion and that this beneficial action is substantially enhanced when the drug's hypotensive effect is prevented.