Clinical trials of the new antiarrhythmic agent encainide have demonstrated a high degree of efficacy in association with marked slowing of intracardiac conduction (prolongation of QRS). Indirect evidence has strongly suggested that at least some of these effects are mediated by the O-demethyl metabolite. The activity of a series of dosages of O-demethyl encainide, encainide and procainamide were compared against aconitine-induced ventricular arrhythmias in rats. Effective dosages were lowest for O-demethyl encainide and highest for procainamide: a 25% increase in the time to aconitine-induced ventricular tachycardia was produced by 0.02, 0.46 and 13 microM/kg of O-demethyl encainide, encainide and procainamide, respectively. QRS prolongation correlated well (r greater than 0.7, p less than .001) with enhanced survivorship for each agent tested and the cycle length of the ventricular tachycardia induced was lengthened in a dose-related fashion. Post-mortem plasma analysis showed that concentrations of the metabolite usually associated with pharmacological activity were present after encainide administration. However, encainide itself produced antiarrhythmic and electrocardiographic effects even when its metabolism was blocked. We conclude that both O-demethyl encainide and encainide exert antiarrhythmic actions in this model, but the metabolite is active at much lower dosages.