MRI investigations in patients with temporal lobe epilepsy (TLE) with mesial temporal sclerosis (MTS) have demonstrated structural abnormalities extending beyond ipsilateral hippocampus which may be studied through voxel-based morphometry (VBM). We investigated brain morphology related to clinical features in patients with refractory TLE with MTS using VBM. One hundred patients with unilateral TLE with MTS (59 left) and 30 controls were enrolled. VBM5 was employed to analyze (1) hemispheric damage, (2) influence of initial precipitating injury (IPI): 23 patients with febrile seizures and 19 with status epilepticus, and (3) types of auras classified as: mesial, including psychic auras (19 patients); anterior mesio-lateral, as autonomic symptoms, specially epigastric auras (27 patients) and neocortical, which included auditory, vertiginous, somatosensory and visual auras (16 patients). (1) Left TLE patients presented more widespread gray matter volume (GMV) reductions affecting ipsilateral hippocampus, temporal neocortex, insula and also left uncus, precentral gyrus, thalamus, parietal lobule, cuneus and bilateral cingulum. (2) Febrile seizures group presented ipsilateral GMV reductions in hippocampus, neocortical temporal, frontal and occipital cortices, insula and cingulum. Status epilepticus group presented more widespread GMV reductions involving temporal and extratemporal lobes. (3) Patients with mesial auras showed significant ipsilateral GMV reductions in hippocampus and amygdala, particularly right TLE group, who presented greater extension of GMV reduction in the entorhinal cortex. Significant reductions in hippocampus, amygdala and insula were seen in patients with anterior mesio-lateral auras. This study evaluated a large number of TLE-MTS patients showing structural damage extending beyond hippocampus, and different types of IPI associated with the extension of brain damage. Subtypes of auras are related to different clusters of areas of GMV reductions in VBM. For the first time, we have demonstrated GMV reductions anatomically correspondent to psychic (mesial areas) and autonomic auras (mesial and insular areas) reproducing previous cortical stimulation studies.