Object: Hypothalamic hamartomas (HHs) often cause pharmacoresistent epilepsy, incapacitating behavioral abnormalities, and cognitive decline. Surgical intervention offers the patient the best opportunity of seizure resolution, which occurs in approximately 50%-60% of patients, and improvement in both cognitive and behavioral difficulties. For those in whom the initial operation has failed, further medical treatment options remain quite limited, whereas, in some cases, a second surgery may improve seizure outcome. The authors retrospectively reviewed their surgical cases to document the success rate and complications of reoperations in patients with HHs. Methods: Data were obtained from the HH epilepsy surgery database at the Barrow Neurological Institute between 2003 and 2010. Surgical treatment consisted of open and endoscopic procedures, as well as radiosurgery. Demographic details, seizure history, presurgical evaluation, and postoperative follow-up data were evaluated. Results: In the last 7 years, 21 (13%) of 157 patients underwent reoperation after an initial epilepsy operation. The initial surgical approach in the 21 patients included: endoscopic (8 patients [38%]), transcallosal (8 patients [38%]), orbitozygomatic (3 patients [14%]), and radiosurgery (2 patients [10%]). Of the 8 patients who initially underwent endoscopic resection, repeat procedures included: radiosurgery in 4 (50%), an orbitozygomatic approach in 2 (25%), repeat endoscopy in 1 (12.5%), and a transcallosal approach in 1 (12.5%). Repeat procedures after an initial transcallosal resection included: endoscopic resection in 2 (25%); radiosurgery in 1 (12%); an orbitozygomatic approach in 2 (25%), and repeat transcallosal surgery in 3 (38%). Predominant seizure types that recurred after the first surgery were gelastic seizures, complex partial seizures, and tonic-clonic seizures. Magnetic resonance imaging in all patients prior to reoperation demonstrated either residual HH and/or connection with the mammillary bodies. Review of patients with more than 6 months of follow-up since the last surgery showed greater than 90% reduction in seizures in 4 patients (19%) and by 50%-90% in 10 patients (48%). Two patients were seizure free, and in 5 patients (24%) there was no change in seizure frequency. Following reoperation, none of the patients had any worsened behavioral issues such as increased rage attacks or disruptive violent behavior. New postoperative complications after reoperation included hemiparesis, thalamic stroke (asymptomatic and symptomatic), hyperphagia, and panhypopituitarism. Conclusions: Reoperation should be considered in selected patients with HH in whom initial epilepsy surgery fails because more than half the patients have significant reductions in seizure.