Cumulation of encainide and its major metabolites, O-demethylencainide (ODE), 3-methoxy-ODE (MODE) and N-demethylencainide (NDE) was examined in patients with frequent complex ventricular ectopy. After 6 mo. on encainide patients were admitted and the drug discontinued for 24 h. During this time blood samples were drawn to characterize the cumulation and disposition of the drug and metabolites. The mean steady-state concentrations of encainide, ODE and MODE were 56.3, 214.6 and 184.6 ng/ml after doses ranging from 100-250 mg/day. The concentration ratios of ODE/encainide and MODE/encainide were 5.02 .+-. 2.61 and 5.15 .+-. 4.13. NDE was detected in the plasma of only 1 patient. Elimination half-lives of encainide and ODE were 1.16 .+-. 0.5 and 11.41 .+-. 9.58 h. MODE disappeared slowly at 24 h the plasma concentration was still 59.8 .+-. 39.9% of its mean steady-state concentration. Evidently, the metabolites of encainide cumulate in the plasma of patients on long-term oral therapy and must be considered when evaluating its clinical efficacy.