We studied 31 consecutive patients with temporal and extratemporal epilepsy who underwent presurgical evaluation with stereotaxic depth EEG (SEEG) to assess the relationships between amygdalo-hippocampal (AM-HF) atrophy and the location of SEEG seizure onset and SEEG interictal abnormalities. Scalp EEG recordings with sphenoidal electrodes had shown bitemporal ictal or interictal epileptic abnormalities in all. Patients underwent high quality MRI scans, including MRI volumetric measurements of mesial temporal structures. None had foreign tissue lesions. The final conclusions of the SEEG investigation coincided with the lateralization obtained by MRI volumetric measurements in the eight patients who had significant unilateral atrophy of the amygdala, hippocampus or both (> 2 SD below the mean of controls). In these patients with unilateral atrophy, all or > 75% of clinical seizures originated from the atrophic side. The seven patients with bilateral, but significantly asymmetrical, mesial atrophy had bilateral seizure onsets with > 70% originating from the more atrophic side in four, from the less atrophic side in two, and without predominance in one. The one patient with severe bilateral symmetrical atrophy had seizures originating equally from both sides. Five patients had no atrophy on MRI, but depth electrodes revealed predominant unilateral ictal temporal onsets in four of them. There was no significant correlation between the frequency of SEEG interictal spikes and the amount of AM-HF atrophy. However, we found a significant correlation between the severity of SEEG background disturbance in AM and HF and the degree of atrophy of these structures. Patients with unilateral atrophy were more frequently free of seizures after surgery than those with bilateral or no atrophy (P < 0.05). We conclude that unilateral mesial atrophy predicts ipsilateral mesial SEEG seizure onset despite bitemporal extracranial EEG foci. However, in patients with significant bilateral mesial atrophy, SEEG seizures may originate from either side, even in the presence of significant asymmetry. Finally, the identification of unilateral mesial atrophy has prognostic importance.