A temporal resection in patients with periventricular nodular heterotopia (PNH) and intractable focal seizures yields poor results. To define the role of heterotopic grey matter tissue in epileptogenesis and to improve outcome, we performed stereoencephalography (SEEG) recordings in eight patients with uni- or bilateral PNH and intractable focal epilepsy. The SEEG studies aimed to evaluate the most epileptogenic areas and included the allo- and neocortex and at least one nodule of grey matter. Interictal spiking activity was found in ectopic grey matter in three patients, in the cortex overlying the nodules in five and in the mesial temporal structures in all. At least one heterotopion was involved at seizure onset in six patients, synchronous with the overlying neocortex or ipsilateral hippocampus. Two patients had their seizures originating in the mesial temporal structures only. Six patients had surgery and the resected areas included the seizure onset, with follow-up from 1 to 8 years. An amygdalo-hippocampectomy was performed in two (Engel class Id and III), an amygdalo-hippocampectomy plus removal of an adjacent heterotopion in two (class Ia), and a resection of two contiguous nodules plus a small rim of overlying occipital cortex in one patient (class Id). One patient with bilateral PNH had three adjacent nodules resected and an ipsilateral amygdalo-hippocampectomy resulting in a reduction of the number of seizures by 25-50%. The best predictor of surgical outcome is the presence of a focal epileptic generator; this generator may or may not include the PNH. Invasive recording is required in patients with PNH; it improves localization and is the key to better outcome.