Hippocampal sclerosis in temporal lobe epilepsy (TLE) is often associated with hippocampal atrophy. This study assessed whether such atrophy is correlated with loss of gray matter volume in other brain regions. In 16 patients with TLE and clear magnetic resonance imaging-based evidence of hippocampal sclerosis, hippocampal volumes were determined manually and the local gray matter (LGM) amount was estimated throughout the entire brain using voxel-based morphometry. Voxelwise correlations between the volume of the sclerotic hippocampus and LGM were computed. The pattern of voxels whose LGM correlated with hippocampal volume outlined remarkably well the anatomy of the extended limbic system and included the parahippocampal region, cingulate gyrus throughout its extent, basal forebrain, thalamic nuclei, medial orbitofrontal areas and the insula. These correlations emerged mainly on the side ipsilateral to the affected hippocampus but were also found contralaterally. No such correlations were found in a group of 16 healthy controls. The present data show that hippocampal volume loss in TLE is associated with a widespread limbic systems atrophy. These findings are helpful to better understand the functional deficit and reorganization often found in temporal lobe epilepsy and will also provide a basis to assess neural plasticity in the limbic system for those patients who will undergo curative temporal lobe surgery.