Objective: To evaluate the relationship between hippocampal volume loss, depression, and epilepsy. Background: There is a significantly increased incidence of depression and suicide in patients with epilepsy. Both epilepsy and depression are associated with reduced hippocampal volumes, but it is uncertain whether patients with both conditions have greater atrophy than those with epilepsy alone. Previous studies used depression measures strongly weighted to current state, and did not necessarily assess the influence of chronic major depressive disorder ("trait"), which could have a greater impact on hippocampal volume. Methods: Fifty-five epilepsy patients with complex partial seizures (CPS) confirmed by electroencephalography (EEG) had three-dimensional (3D)-spoiled gradient recall (SPGR) acquisition magnetic resonance imaging (MRI) scans for hippocampal volumetric analysis. Depression screening was performed with the Beck Depression Inventory (BDI, 51 patients) and with the structured clinical inventory for DSM-IV (SCID, 34 patients). For the BDI, a score above 10 was considered mild to moderate, above 20 moderate to severe, and above 30 severe depression. MRI and clinical analysis were performed blinded to other data. Statistical analysis was performed with Systat using Student's t test and analysis of variance (ANOVA). Results: There was a significant interaction between depression detected on SCID, side of focus, and left hippocampal volume. Patients with a diagnosis of depression and a right temporal seizure focus had significantly lower left hippocampal volume. A similar trend for an effect of depression on right hippocampal volume in patients with a right temporal focus did not reach statistical significance. Conclusions: Our results suggest that patients with right temporal lobe epilepsy and depression have hippocampal atrophy that cannot be explained by epilepsy alone.