The efficacy of oral disopyramide and mexiletine used alone or in combination was studied in 75 patients with frequent ventricular premature beats (VPBs). The efficacy was evaluated with 24-hour ambulatory ECG and > 75% reduction in the number of VPBs was defined as effective. When disopyramide or mexiletine were ineffective or not tolerated, the alternative drug was administered and the efficacy was again evaluated. If the single administration of nei. ther drug was effective, the combination of disopyramide and mexiletine was then given. Either disopyramide or mexiletine was effective in 48 patients, and neither drug was effective in 19 patients. In 19 patients unresponsive to both drugs, combination therapy was effective in six patients (32%). Both drugs caused side effects or one drug caused side effects and another drug was ineffective in eight patients. In five out of those patients, we attempted combined therapy with a reduced dosage of those drugs that caused side effects. This therapy was effective in two patients without intolerable side effects. Thus, when the single use of neither disopyramide nor mexiletine single-drug therapy is effective, it is worthwhile to try combination therapy. Also, combination therapy with a reduced dosage of the drugs that caused side effects might be the therapy of choice in patients who have developed dose-dependent side effects.