Primidone (PRM) kinetics was examined in two groups of adult seizure patients: (1) 10 newly diagnosed in whom only PRM was used, the monotherapy (MT) group, and (2) nine in whom PRM was added to other antiepileptics, the combination therapy (CT) group. Time-concentration data were obtained after an initial dose pf 250 mg and during subsequent steady-state periods. PRM elimination was slower (p < 0.05) after the initial dose in MT patients (half-life (t 1 2) = 15.2 hr, apparent clearance = 35 ml/hr/kg) than in CT patients (t 1 2 = 8.3 hr, clearance = 51 ml/hr/kg). PRM metabolites, phenobarbital and phenylethylmalonamide, appeared much earlier in CT patients. Continued PRM exposure in MT patients was accompanied by an increase in apparent clearance in three of seven patients, but no change in four of seven. In four CT patients in whom other antiepileptics were withdrawn there was a decrease in apparent clearance (61.4 to 29.9 ml/hr/kg) to rates in the range of MT patients. PRM kinetics is influenced by concurrent antiepileptic drugs and by duration of PRM therapy.