The tricyclic antidepressant drug imipramine may cause ventricular arrhythmias and intraventricular conduction disturbances in clinical use, particularly in patients who have ingested toxic doses or who have preexisting heart disease. Such effects have not been reported with doxepin, another tricylic antidepressant drug. In this study, the electrophysiologic effects of these two drugs on normal and depressed canine Purkinje fibers were examined. Fiber depression was achieved by elevating potassium concentration [K+] in the perfusate to 10 mM. In normal Purkinje fibers both imipramine and doxepin were tested in concentrations of 50, 250, 500 and 1,000 ng/ml. Both drugs had no effect on resting membrane potential but caused similar, dose-related reductions in action potential amplitude, maximal velocity of phage O depolarization (Vmax), action potential duration, conduction velocity and effective and functional refractory periods. Depressed fibers were exposed to only 250 ng/ml of imipramine and doxepin. Both drugs reduced conduction velocity and failed to alter the refractory periods of the depressed fiberts whereas at the same concentration in normal fibers they caused no change in conduction velocity but shortened the refractory periods. The other electrophysiologic effects of the two drugs on depressed fibers were similar to those on normal fibers. These observations indicate that depressed fibers are more sensitive than normal fibers to certain electrophysiologic effects of both imipramine and doxepin, and that the different incidence rates of arrhythmias and conduction disturbances associated with the clinical use of these drugs is probably not due to differences in their direct electrophysiologic effects on the ventricular specialized conduction system.