Mesial temporal sclerosis (MTS) is the most common cause of medically intractable temporal lobe epilepsy. Histologic findings include hippocampal atrophy with neuronal loss in the dentate, CA1, and CA3/CA4 regions with gliosis. The conventional treatment of patients with intractable epilepsy secondary to MTS has been surgical excision. Gamma knife radiotherapy (GKR) has recently been suggested as a less invasive alternative to surgery. To date, the histologic changes that occur in this setting after GKR have not been well described. The clinicopathologic features of 4 patients with MTS who received GKR and underwent subsequent surgical resection or autopsy were retrospectively reviewed. The study group is composed of 4 patients (3 women, 1 men) with ages 55, 48, 22, and 20 years, respectively, at the time of GKR. There were 2 patients who had a history of infantile febrile seizures, and 2 who had a central nervous infection during infancy. All 4 patients had a long-standing (13-36 years) history of temporal lobe seizures resistant to medical management. Imaging studies, electroencephalogram, and surgical specimens all confirmed the diagnosis of MTS. The oldest of the 4 patients died 1 month after receiving GKR, presumably because of post-gamma knife persistent seizure complications. The postmortem neuropathology on this patient was unremarkable for any radiation effect changes but showed evidence of MTS. The remaining 3 patients underwent surgical resection for persistent seizures at 18, 22, and 20 months, respectively, post-gamma knife. These 3 surgical specimens showed variable degrees of radiation effect changes in the temporal lobe, hippocampus, and amygdala, including chronic (lymphocytes and macrophages) perivascular inflammation (3/3), vascular sclerosis (3/3), foci of edema with necrosis (3/3; extensive in 2 patients), reactive astrocytosis (3/3), microglial proliferation (1/3), and microcalcifications (1/3). Patients with MTS who underwent GKR can develop typical radiation changes over time. Treatment of individuals with MTS via GKR may not always be adequate in controlling seizures. Radiation therapy effect may contribute to persistent seizures after GKR in some patients with MTS.