To assess the antiarrhythmic effect of lorcainide and determine whether there is a pharmacokinetic interaction between lorcainide and digoxin, 12 patients with frequent premature ventricular depolarizations (PVDs) who were taking digoxin were treated with lorcainide. During a placebo period, serum digoxin concentration was measured for three days; plasma lorcainide concentration, a 12-lead electrocardiogram (ECG), and a 24-hour continuous ECG were measured on the day before the patients began lorcainide and repeated on days 3, 7, and 14 of treatment. Lorcainide was given 100 mg bid or 100 mg tid. Lorcainide did not suppress group mean PVDs per hour, pairs, or ventricular tachycardia. Only four patients (33%) responded with greater than or equal to 80% suppression of PVDs. Mean ejection fraction for responders was 46 +/- 6%, and for nonresponders it was 28 +/- 9% (P less than .01). There was no significant pharmacokinetic interaction between lorcainide and digoxin. Mean digoxin concentration did not change after lorcainide administration; two patients had greater than or equal to 50% increase in serum digoxin concentration. Patients with heart failure or reduced ejection fraction define a subset who have unpredictable effects from lorcainide, including a reduced antiarrhythmic effect.