The prevalence and severity of psychopathology in 15 epileptic patients treated with phenobarbital and 24 patients treated with carbamazepine were compared. The groups were similar across a wide range of demographic, seizure-related, and family-environmental variables. Patients treated with phenobarbital, when compared with those treated with carbamazepine, showed a much higher prevalence of major depressive disorder (40% v 4%, P = .02), and suicidal ideation (47% v 4%, P = .005) as determined by semistructured psychiatric interviews. The differential prevalence of depression between medication groups was only noted in those with a family history of a major affective disorder among first-degree relatives. Family discord and number of stressful life events were also associated with depression in this cohort. Patients treated with phenobarbital should be closely monitored for depression, and alternative treatments should probably be sought for patients with newly diagnoses epilepsy and a personal or family history of an affective disorder. The clinical and research implications of these findings are discussed.