The efficacy of mexiletine used alone, and in combination with a class la antiarrhythmic drug, was assessed in 159 previously drug-refractory patients with ventricular tachycardia (VT) during serial electrophysiologic studies and during long-term (5-year) clinical follow-up. Electrically-inducible ventricular tachycardia was suppressed by mexiletine alone in 23% of patients tested, and a combined antiarrhythmic drug regimen was effective in 29% of the trials performed. Mexiletine was much more likely to be effective in patients presenting with nonsustained VT or ventricular fibrillation than in patients with sustained VT (p < 0.005). After 1 and 4 years of treatment, 18% and 42% of the patients treated with mexiletine alone had died suddenly or suffered recurrent symptomatic VT, compared to 11% and 25% of patients treated with the combined antiarrhythmic drug regimens (p=NS). Mexiletine therapy was associated with frequent, though readily reversible, adverse reactions. However, mexiletine treatment had to be discontinued permanently in 8 of 92 patients (9%) because of intolerable side effects. We conclude that the added efficacy and possible improved arrhythmia-free survival associated with combining mexiletine with a class la agent should be further investigated.