PURPOSE: Although gamma-knife radiosurgery (GKS) has proved efficacious in temporal lobe epilepsy (TLE), its antiepileptic mechanism of action remains elusive. Human and experimental data suggest that subnecrotic radiation-induced tissue changes might contribute to the antiepileptic effect of GKS. However, there are no data regarding the evolution of electroencephalography (EEG) activity within GKS-treated hippocampus, information that aid in better understanding both the mechanism of action and the reason for failure of GKS treatment. METHODS: Two patients with disabling seizures 4 and 6 years after mesial temporal GKS with a marginal dose of 24 Gy were investigated with stereotactic intracerebral EEG recordings. Both patients had right TLE with hippocampal atrophy, but with past history of Coxsackie virus meningoencephalitis and congenital toxoplasmosis, respectively. Ten to 12 electrodes were implanted, including seven to eight electrodes within the epileptic temporal lobe. KEY FINDINGS: In both patients, depths electrodes placed within the irradiated mesial temporal structures disclosed a remarkable pattern of subcontinuous spiking activity intermingled with asymptomatic rhythmic discharges up to 1 min in duration. This activity differed from the abnormalities usually captured in mesial TLE (mTLE) and suggested radiosurgery-induced brain changes. Both patients underwent anterior temporal lobectomy and achieved a class I outcome after a follow-up of 18 and 40 months, respectively. Pathologic examination of the surgical specimens showed variable degrees of radiation-effect changes. SIGNIFICANCE: Our study shows that mesial temporal structures previously treated with GKS can demonstrate a persistent high degree of epileptiform activity in patients who failed to respond to that treatment. Although this persistent EEG activity appears likely to reflect GKS-induced brain changes, its relation to GKS seizure outcome remains unclear.