We studied the effects of bretylium tosylate and lidocaine on ventricular fibrillation in the isolated, perfused rabbit heart induced by perfusion with potassium-deficient solutions and by premature stimuli. The purpose of the study was to determine if the reported antifibrillatory effects of the drugs could be reproduced in the absence of an intact sympathetic nervous system. Lidocaine in the concentration of 5 mug/ml. prevented ventricular fibrillation induced by both methods while bretylium, in concentrations of 25 to 50 mug/ml. prevented neither type of filbrillation. These results indicate that the antifibrillatory effects of lidocaine can be attributed to drug-induced alterations in cellular electrophysiology, whereas those of bretylium are independent of such changes. Our study suggests that the reported antifibrillatory capability of bretylium is related to the drug's effects at sympathetic nerve terminals and thus is dependent upon an intact sympathetic nervous system.