Previous investigations have shown that a slower heart rate (HR) and myocardial ischemia independently diminish the electrical stability of the heart. It therefore was suggested that increasing heart rate during myocardial infarction might diminish the incidence of serious ventricular arrhythmias. However, since increased HR during experimental acute myocardial ischemia augments the degree of ischemia, an evaluation of the presumed "protective" effects of increased HR on the electrical stability of acutely ischemic myocardium was undertaken. The differences in refractory periods (RP) of eight contiguous areas of the left ventricle were determined as a function of HR. In nonischemic myocardium, the disparity of RP was less at an HR of 180 than 60. However, in ischemic myocardium the disparity increased in three of six animals as the HR was increased from 60 to 90, in seven of 10 animals as HR was increased from 60 to 120, and in all animals when the HR was increased from 60 to 180. The increased disparity of RP is believed to favor development of reentrant arrhythmia. The vulnerability of the heart to develop ventricular fibrillation was assessed by determining ventricular fibrillation threshold (VFT). During ischemia, VFT was not only an inverse function of HR but also was found to be independently influenced by electrical stimulation of the cervical vagus nerves. In the absence of vagal stimulation VFT was lowered in only one of four dogs as HR was increased from 50 to 90, but decreased 30% (P < 0.01) as HR reached 120 and 74% at 180 beats/min. When vagal stimulation was used to control HR VFT was lowered 37% as HR was increased from 50 to 60 to 90 (P < 0.05). We conclude that increasing HR within a physiologic range by diminishing vagal tone during myocardial ischemia decreases electrical stability of the ventricle by (1) increasing ischemia consequent to the rate-induced increase in myocardial oxygen requirements, and (2) a direct electrophysiologic action of the vagus on the ventricular myocardium.