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Objective Epilepsy with periventricular nodular heterotopia (PVNH) lacks a conclusive surgical treatment strategy as eloquent cortex and important white matter tracts frequently overlay the deep periventricular nodules. Our goal was to evaluate the safety and efficacy of laser interstitial thermal therapy (LITT) for the treatment of epilepsy in PVNH. Methods Data on demographic characteristics, complications, visual outcomes, Engel classification at last follow-up, antiepileptic drug use, morbidity, and mortality among patients who underwent this procedure were retrospectively reviewed. Results Between May 2015 and January 2019, 5 patients underwent 6 LITT procedures for epilepsy with PVNH. One patient had residual nodules after their first procedure and underwent a second ablation. The average follow-up time was 12 months. Three patients were Engel class Ia, 1 patient was Engel class II, and 1 patient was Engel class III at last follow-up. Two patients were able to reduce their antiepileptic drugs postoperatively. Three patients had no changes in vision, 1 patient experienced a quadrantanopsia, and 1 patient had subjective blurry vision after their procedures. No patients experienced motor deficits, dysphasia, infection, or mortality. Conclusions LITT appears to be a safe and promising option to provide seizure relief for patients with refractory epilepsy and PVNH that otherwise may not be surgical candidates. Some appropriately determined patients with refractory epilepsy may benefit from LITT before proceeding with an invasive intracranial evaluation. A larger sample size and long-term follow-up is necessary to further elucidate safety and efficacy.