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Objective Tuberous sclerosis complex (TSC) is a genetic disorder primarily characterized by the development of multisystem benign tumors. Epilepsy is the most common neurologic manifestation, affecting 80%‐90% of TSC patients. The diffuse structural brain abnormalities and the multifocal nature of epilepsy in TSC pose diagnostic challenges when evaluating patients for epilepsy surgery. Methods We retrospectively reviewed the safety experience and efficacy outcomes of five adult TSC patients who were treated with direct brain‐responsive neurostimulation (RNS System, NeuroPace, Inc). Results The average follow‐up duration was 20 months. All five patients were responders (≥50% disabling seizure reduction) at last follow‐up. The median reduction in disabling seizures was 58% at 1 year and 88% at last follow‐up. Three of the five patients experienced some period of seizure freedom ranging from 3 months to over 1 year. Significance In this small case series, we report the first safety experience and efficacy outcomes in patients with TSC‐associated drug‐resistant focal epilepsy treated with direct brain‐responsive neurostimulation.