OBJECTIVE: We hypothesized that total brain volume, white matter volume, and lobar cortical thickness would be different in epilepsy patients. We studied valproate relative to nonvalproate by using patients with epilepsy and healthy controls. METHODS: Patients with focal intractable epilepsy from a tertiary epilepsy center were the primary group for analysis. A confirmatory analysis was carried out in an independent group of subjects imaged as part of a community-based study of childhood-onset epilepsy. Total brain volume; white matter volume; and frontal, parietal, occipital, and temporal lobe thickness were measured by processing whole-brain T1-weighted MRI using FreeSurfer 5.1. RESULTS: Total brain volume, white matter volume, and parietal thickness were reduced in the valproate group relative to controls and nonvalproate users (valproate, n = 9; nonvalproate, n = 27; controls, n = 45; all male). These findings were confirmed in an independent group (valproate, n = 7; nonvalproate, n = 70; controls, n = 20; all male). CONCLUSIONS: Sodium valproate use in epilepsy is associated with parietal lobe thinning, reduced total brain volume, and reduced white matter volume. LEVEL OF EVIDENCE: This study provides Class IV evidence that use of valproate in epilepsy is associated with reduced parietal lobe thickness, total brain volume, and white matter volume.