The antiarrhythmic efficacy and safety of oral mexiletine hydrochloride and quinidine sulfate were compared at 29 clinical centers in a double-blind, parallel-group trial involving 491 patients with benign or potentially lethal ventricular arrhythmias. Responders were defined as those who had at least a 70% reduction in the frequency of ventricular premature complexes (VPCs) that persisted for 12 weeks, and who experienced no intolerable side effects that required discontinuation of therapy. Of the patients available for analysis, 71 of 232 (31%) in the mexiletine and 73 of 225 (32%) in the quinidine group met these criteria. The dose range used for mexiletine was 200 to 400 mg every 8 hours, and that for quinidine 200 to 400 mg every 6 hours. More than half of the patients in each group were successfully treated with the smallest dose (200 mg every 8 hours mexiletine vs 200 mg every 6 hours for quinidine). Quinidine significantly prolonged the QT interval, whereas mexiletine did not. Proarrhythmic reactions were recorded in 18 of 221 (9%) patients taking quinidine and 10 of 217 (5%) patients taking mexiletine. There was no difference in the incidence of adverse reactions between the 2 groups; in both, the most common side effects were related to the gastrointestinal and central nervous systems. Mexiletine thus represents an alternative to quinidine for the treatment of patients with ventricular arrhythmias.