The effect of flecainide, 200 mg twice daily for 5 days, on steady-state plasma digoxin levels was determined in 15 healthy male subjects who received 0.25 mg of digoxin per day. The predose mean plasma digoxin level before flecainide administration on days 9 and 10 was 0.46 ng/ml, compared with 0.57 ng/ml on day 13 (p < 0.05) and 0.49 ng/ml on day 15 (difference not significant [NS]) when flecainide was given concurrently with digoxin. The 6-hour postdose mean level for days 9 and 10 was 0.58 ng/ml, compared with mean levels of 0.62 ng/ml on day 13 (NS) and 0.65 ng/ml on day 15 (p < 0.05). On average, predose and 6-hour postdose digoxin levels increased by 24 ± 35% and 13 ± 19%, respectively, during co-administration. A significant prolongation of the electrocardipgraphic PR interval in 6 of 15 subjects was noted on the combined drug dosage. This reverted to normal after cessation of drug administration. Vital signs showed no significant clinical change during the course of the study. Ten other healthy male subjects were given propranolol, 80 mg 3 times daily, or flecainide, 200 mg twice daily, alone or in combination. Effects on vital signs, exercise heart rate, electrocardiographic interval, M-mode indexes of ventricular function and plasma drug levels were monitored to determine effects of the study drugs when given separately or concurrently. Both drugs caused a decrease in blood pressure, with the systolic pressure affected more than the diastolic; the effects of propranolol and flecainide were additive. Propranolol markedly decreased the pulse rate; flecainide increased the pulse rate slightly; concomitant effects were additive. The electrocardiographic PR interval was prolonged by both drugs; concomitant administration gave a subadditive effect. Echocardiographic changes were consistent with a negative inotropic effect, with propranolol more active than flecainide; concomitant effects were additive. Average plasma drug levels (AUC values) for both propranolol and flecainide were elevated somewhat (≤ 30%) by concurrent administration; the increases were not associated with any synergistic cardiodynamic effects. Plasma half-life was not altered for either drug by co-administration.