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Cavernous malformations (CMs) are congenital vascular malformations of the brain, which often present with drug-resistant epilepsy. Microsurgical excision remains the preferred approach for cortical-subcortical epileptogenic CMs that are not located in functional cortex. For patients presenting with seizures arising from eloquent cortex surrounding the lesion, radiosurgery appears to be a suitable alternative. We evaluated the effectiveness of Gamma Knife (GK) surgery in the management of drug-resistant seizures associated with CMs in a retrospective multicenter study. Forty-nine patients with cortical or subcortical CMs with severe long-term drug-resistant epilepsy underwent radiosurgery. The mean duration of epilepsy before these GK procedures was 7.5 (±9.3) years. The mean frequency of seizures was 6.9/month (±14). The mean marginal radiation dose was 19.17 Gy. At the last follow-up examination, 53% were seizure free. A highly significant decrease in the number of seizures was achieved for another 20%. The remaining 26% of patients showed little or no improvement. The morbidity was low. Radiosurgery is a promising management modality for epilepsy associated with CMs. The determination of the extent of the epileptogenic zone in CMs and dose selection are the critical steps towards successful radiosurgical outcome. Further prospective work is necessary to validate our data., (Copyright © 2013 S. Karger AG, Basel.)