Mood disorders, including depression, are the most common comorbid conditions in epilepsy,1,2 and impose substantial burdens including reduced quality of life, increased disability and healthcare utilization,3 and heightened risk for suicidal ideation and attempts.4 Moreover, individuals with comorbid mood disorders tend to have a worse seizure outcome than those without comorbid mood disorders.5 Although the comorbidity of epilepsy and mood disorders has been extensively studied, the cause of the comorbidity needs further clarification. One possible explanation is the chronic psychosocial impact of epilepsy, including social stigma,6 learned helplessness, and lack of control.7 Moreover, epilepsy can lead to an acute state of depressed mood due to side effects of antiepileptic drugs8 or seizure manifestations.9 Finally, the comorbidity may be due to an underlying shared neurobiological pathogenesis, possibly involving the limbic system10,11 or neurotransmitter function.12 Demonstration of the “bidirectionality” of the association (ie, an increased risk of mood disorders in persons with epilepsy both before and after onset of epilepsy) supports the concept of shared pathogenic mechanisms.13 We took advantage of an ongoing study of familial epilepsy14 to investigate the hypothesis that the comorbidity between epilepsy and mood disorders is due, in part, to a shared genetic susceptibility. Few studies have investigated this hypothesis. In our previous study of families with autosomal dominant epilepsy with auditory features (ADEAF) with mutations in the leucine-rich, glioma inactivated 1 gene (LGI1),15 rates of current depressive symptoms were increased among mutation carriers with epilepsy, but not among mutation carriers without epilepsy. In another study, a family history of epilepsy was associated with affective disorders among individuals with childhood onset epilepsy.16 However, neither study used a full diagnostic instrument nor assessed lifetime history of mood disorders, which is most important for assessing shared genetic risk. In the current study, we used the Composite International Diagnostic Interview (CIDI)17 to assess the lifetime prevalence of mood disorders in a set of families enriched for genetic influences on epilepsy because they contained multiple affected individuals. To evaluate evidence for a shared genetic susceptibility to epilepsy and mood disorders, we assessed the lifetime prevalence of mood disorders in relatives without epilepsy in these families, and compared it with lifetime prevalence in a general population sample. We also compared the lifetime prevalence of mood disorders in individuals with versus without epilepsy in these families (overall and by broadly defined epilepsy types), and assessed the relationship of lifetime prevalence of mood disorders to the type of epilepsy in the family.