We performed a retrospective study of the effect of antidepressant treatment with doxepin on seizure frequency. From 47 patients treated with doxepin in 3 years, a confirmed seizure disorder and adequate follow-up (mean, 6.8 months) were available for 19 patients. Comparison of mean monthly seizure frequency during equal blocks of time before and during treatment with doxepin in doses of 5 to 400 mg/ day demonstrated improved seizure control in 15, no change in 2, and increased seizures in 2 patients. The reduction in seizure frequency may have been a result of a direct antiepileptic effect of doxepin, an indirect effect because of improved affective state, drug interactions, or some combination of these mechanisms.