Interictal depression is common among epilepsy patients and may have a relationship to seizure variables. Among 1339 epileptic outpatients, we identified 101 (7.5%) patients who had a depressive disorder that required psychiatric evaluation, compared with only 105 (5.3%) of 1991 migraine patients from the same clinic (p = .01). The 101 epilepsy-depression patients were compared retrospectively with 202 seizure patients without depression on six seizure variables. The epilepsy-depression group had significantly fewer patients with generalized tonic-clonic seizures, a decreased frequency of generalized tonic-clonic seizures, and more patients on multiple anticonvulsant medications. We conclude that interictal depression in epilepsy may result from the use of more anticonvulsant drugs resulting in the prevention of secondary generalization from a seizure focus.