Medial temporal lobe epilepsy (MTLE) is associated with hippocampal cell loss and organization of the dentate gyrus. Some studies suggest a correlation between the topographic distribution of cell loss and site of epileptogenesis. We studied the relationship between the site of ictal onset with the presence of segmental atrophy in patients with non-lesional MTLE using magnetic resonance imaging (MRI) and depth EEG. Ictal recordings were obtained from 27 patients with longitudinal hippocampal depth electrodes and variable combinations of subdural strips sampling medial temporal structures. The location of the depth electrode contacts was correlated with anatomical landmarks. Seizures were analyzed for the distribution of onset along the long axis of the hippocampus. MRI analysis were performed to detect segmental atrophy. Outcome was assessed 1 year or more following anterior temporal lobectomy. Twenty-five patients had unilateral, and two had bilateral, hippocampal atrophy. One hundred and forty-seven seizures were reviewed: 21 showed focal onset and 126 showed regional onset. Ictal onset involved the amygdala and anterior half of the hippocampus in 80% of the seizures while only 40% of patients had atrophy of these segments. Most patients had excellent outcome. In patients with MTLE the primary area of epileptogenesis does not parallel the hippocampal segments with the greatest degree of volume loss.