We compared the electrophysiologic and clinical effects of oral cibenzoline and sotalol in 12 patients with spontaneous and inducible sustained ventricular tachycardia (VT), using a randomized, open-label, cross-over study. Electrophysiologic studies were performed in the control state, after oral cibenzoline and after oral sotalol, using an incremental dose-titration protocol. Therapy with cibenzoline at the maximum dose level (130-390 mg/day) resulted in complete suppression of VT in 1 of 12 patients (8%). Sotalol (160-320 mg/day) prevented induction of VT in 4 of 12 patients (33%). The effective refractory period (ERP) of the right ventricle was more significantly prolonged with sotalol (p < 0.001) as compared with cibenzoline (p < 0.05). Neither drug prolonged QT duration corrected for frequency (QTc) and cycle length of induced VT, as compared with the control study. Three patients experienced spontaneous VT after cibenzoline administration, and 2 patients experienced incessant VT during programmed electrical stimulation. No patient had a proarrhythmic effect while receiving oral sotalol treatment. Chronic sotalol therapy maintained long-term arrhythmia suppression in all 4 responders at 1-year follow-up. Sotalol appears to have greater efficacy than and a safety profile superior to that of cibenzoline. Drug-related proarrhythmic effects of oral cibenzoline therapy occurred with greater frequency than that associated with other antiarrhythmic drugs. Based on these findings, cibenzoline cannot be recommended for use in patients with VT.