The combination of phenobarbital (PB) and phenytoin (PHT) was recommended for many years for treatment of epilepsy in humans. We tested the effectiveness of the combination in a model of hippocampal seizures termed maximal dentate activation (MDA). Two parameters of MDA were measured: duration and time to onset. Neither the vehicle controls nor PHT 80 mg/kg had an effect on duration or time to onset of MDA. PB 20 mg/kg delayed the normal increase in MDA duration and had no effect on time to onset. Addition of increasing doses of PHT to the 20-mg/kg dose of PB caused a dose-dependent decrease in MDA duration and a dose-dependent increase in time to onset. These effects do not appear to be due to an increase in serum level of either drug when administered together. We showed that the combination of PB and PHT has actions in an experimental model of limbic seizures that are not produced by either drug alone. Therefore, clinical use of the combination does have some experimental justification.