The effects of encainide on ventricular arrhythmia and left ventricular function were studied in 21 patients with chronic, high-grade ventricular arrhythmia using a prospective, 3-month, placebo-controlled, single-blind trial design. Encainide caused a 96% decrease in the average hourly frequency of ventricular premature complexes (VPCs) and comparable reductions in salvos of nonsustained ventricular tachycardia (VT) and episodes of sustained VT. Intracardiac electrophysiologic testing showed prolonged intraatrial and intraventricular conduction times and increased atrial, atrioventricular nodal, and ventricular refractory periods with both i.v. and oral encainide without His-Purkinje block, despite marked prolongation of HV and QRS intervals. Induced repetitive ventricular beating after ventricular extrastimuli in 15 patients showed persistent repetitive ventricular beating with chronic oral encainide in seven patients, four of whom had sustained VT within 2 months of treatment on encainide. Encainide did not reduce exercise capacity or left ventricular ejection fraction at rest or during supine exercise. Minor adverse effects of encainide in 11 of 21 patients included dose-related visual disturbances, dizziness and sinus pauses (less than 3 seconds). Major adverse effects included the new appearance of sustained VT in three of 20 patients (15%). Oral encainide effectively reduces the frequency and grade of VPCs, prolongs intracardiac conduction times, and does not impair left ventricular performance. However, it is associated with frequent minor side effects and uncommon but potentially severe major side effects (sustained VT), both of which apparently have a direct relationship to the size of the dose.