Objective: Limited evidence is available to guide treatment of depression for persons with epilepsy. We evaluated the comparative effectiveness of sertraline and cognitive behavior therapy (CBT) for depression, quality of life, seizures, and adverse treatment effects. Methods: We randomly assigned 140 adult outpatients with epilepsy and current major depressive disorder to sertraline or weekly CBT for 16 weeks. The primary outcome was remission from depression based on the Mini International Neuropsychiatric Interview (MINI). Secondary outcomes included the Quality of Life in Epilepsy Inventory-89 (QOLIE-89) seizure rates, the Adverse Events Profile (AEP), the Beck Depression Inventory, and MINI Suicide Risk Module. Results: In the intention-to-treat analysis, 38 (52.8%; 95% confidence interval [CI] = ±12) of the 72 subjects assigned to sertraline and 41 (60.3%; 95% CI = ±11.6) of the 68 subjects in the CBT group achieved remission; the lower bound of efficacy for both groups was greater than our historical placebo control group upper bound of 33.7%. Difference in time to remission between groups was 2.8 days (95% CI = ±0.43; p = 0.79). The percent improvement of mean QOLIE-89 scores was significant for both the CBT (25.7%; p < 0.001) and sertraline (28.3%; p < 0.001) groups. The difference in occurrence of generalized tonic–clonic seizures between groups was 0.3% (95% CI = ±8.6; p = 0.95). Suicide risk at final assessment was associated with persistent depression (p < 0.0001) but not seizures or sertraline. Interpretation: Depression remitted in just over one-half of subjects following sertraline or CBT. Despite the complex psychosocial disability associated with epilepsy, improving depression benefits quality of life. Serotonin reuptake inhibition does not appear to increase seizures or suicidality in persons with epilepsy. ANN NEUROL 2019;86:552–560.