Preparations of papillary muscle and Purkinje fibers were obtained from dog hearts, perfused with oxygenated Tyrode solution in a tissue chamber, and observed both under control conditions and during exposure to bretylium tosylate in concentrations from 1 × 10 −7 M to 1 × 10 −4 M. Transmembrane voltage was recorded from both ventricular muscle and Purkinje fibers in spontaneously beating and in electrically driven preparations. Bretylium did not suppress phase 4 depolarization or spontaneous firing in Purkinje fibers. After application of bretylium to spontaneously firing Purkinje fibers, the rate initially increased by 20 percent; in quiescent fibers, bretylium often induced spontaneous firing. Since neither effect was seen in preparations obtained from dogs treated with reserpine, each was attributed to bretylium-induced release of catecholamines from the adrenergic nerve terminals in the preparations. In concentrations of less than 1 × 10 −4 M, bretylium did not alter the resting transmembrane voltage or the action potential amplitude and overshoot; concentrations of 1 × 10 −4 M caused a decrease in each of these variables. Bretylium, <- 1 × 10 −4 M, had no effect on the maximal rate of rise of phase zero depolarization (peak V́max), membrane responsiveness or conduction velocity in Purkinje fibers. A concentration of 1 × 10 −4 M caused a decrease in peak V́max, shifted membrane responsiveness curves on their voltage axis, and decreased conduction velocity. Over a wide range of stimulation rates (30 to 150/min), bretylium caused a large increase in action potential duration and effective refractory period of both ventricular muscle and Purkinje fiber cells without lengthening the effective refractory period relative to action potential duration. Since bretylium lacked most of the electrophysiologic properties associated with antiarrhythmic drugs, its antiarrhythmic action against ventricular arrhythmias may, to a large extent, be due to its effect on adrenergic nerve terminals.