The effects of ethosuximide and diphenylhydantoin sodium on feline generalized penicillin epilepsy, a model of human generalized corticoreticular (centrencephalic) epilepsy, were compared. Epileptic bursts in the electroencephalogram (EEG) were significantly reduced following administration of ethosuximide with plasma levels of 60 μg per milliliter, and there was a linear correlation between the plasma level and antiepileptic effect (p <0.01). Diphenylhydantoin produced a lesser reduction in epileptic activity, and there was no correlation between the plasma level and effect. Four cats that received both drugs successively responded well to ethosuximide, while only two responded to diphenylhydantoin. The good response to ethosuximide is in accord with clinical experience in human generalized corticoreticular epilepsy.