The vagus nerve modulates electrical activity of the cardiac ventricles. However, whether the vagus nerve mediates these effects through the conduction system or directly on the myocardium is unknown. Accordingly, we studied vagus nerve stimulation (VNS) during sinus rhythm and during ventricular fibrillation (VF) in porcine and ovine preparations. We sought to determine: 1) what is the most potent frequency with which to stimulate the vagus nerve and 2) whether VNS at that frequency produces any change in cardiac wall motion during ventricular fibrillation. We studied 8 pigs and 10 sheep that were anesthetized with urethane 1 mg/kg intravenously and placed on a ventilator. Platinum vagus nerve electrodes were wrapped around the nerves. Simultaneous electrocardiogram (EKG) and carotid artery blood pressure (BP) recordings were made. VNS was performed in animals with 1-millisecond pulses for 20 seconds at 1, 2, 5, 10, 20, 50, and 100 Hz. This was done on both vagus nerves separately and bilaterally. Potency of the VNS was evaluated by counting the number of beats within the 20 seconds. VF was produced in 4 pigs by opening the thorax and applying direct current to the ventricles. Epicardial echocardiography during VF was performed, and both vagus nerves were stimulated at 50 Hz for 20 seconds. Wall motion data was extracted during VF for three periods—before, during, and after VNS. All data are presented as means with S.E.M. and were compared using repeated measures ANOVA, and p-values are reported. Tukey post-hoc analysis was performed, and statistical significance was taken as p-values < 0.05. In both sheep and pigs, 50 Hz was found to be the optimal frequency required to produce cardiac standstill. Bilateral VNS in pigs at 20, 50, and 100 Hz produced 21 ± 13, 1 ± 1, and 24 ± 14 beats in 20 seconds of stimulation, respectively (p = 0.003, 50 Hz was significantly different from 20 and 100 Hz). Bilateral VNS in sheep at 20, 50, and 100 Hz produced 14 ± 6, 2 ± 2, and 18 ± 7 beats in 20 seconds of stimulation, respectively (p = 0.002, 50 Hz was significantly different from 20 and 100 Hz). Wall motion data during VF showed 0.065 ± 0.005, 0.030 ± 0.008, and 0.057 ± 0.004 centimeters mean displacement before, during, and after VNS, respectively (p = 0.005, wall motion during VNS was significantly smaller than the other groups). We conclude that 50 Hz is the optimal frequency for VNS to exert its optimal cardiac effects. Vagus nerve stimulation affects the ventricles in large animals in both sinus rhythm and VF. These findings suggest VNS may provide an alternative adjunct therapy to treat ventricular arrhythmias.