Mesial temporal lobe epilepsy (mTLE) with mesial temporal sclerosis (MTS) is a recognized epilepsy syndrome which is successfully treated with mesial temporal lobe resection. However, recent studies suggest that mTLE is more than a "focal" disease process. The objective of our study was to determine the presence and extent of functional abnormalities outside of a defined structural abnormality in epilepsy patients with mTLE. We used a prospective age-matched controlled design to study eight consecutive patients with MTS who were undergoing epilepsy surgery evaluation. Magnetoencephalography was used to localize the sources of electromagnetic abnormality. Proton magnetic resonance spectroscopy ((1)H-MRS) measured integrated peak areas for N-acetyl compounds (NAA) and choline-containing compounds (Cho) to determine regions of metabolic abnormality. All eight subjects had predominant electromagnetic abnormality in the temporal lobe ipsilateral to the MTS. All eight subjects had lower NAA/Cho ratios in the region of electromagnetic abnormality when compared to the homologous contralateral region (P < 0.001). Four subjects had predominant MEG spiking outside the mesial temporal region. Surgery-free outcome for the group with neuroimaging abnormalities outside of the medial temporal lobe is 50%. The region of maximal electromagnetic abnormality is outside the hippocampus in some patients with mTLE. These regions also demonstrate functional abnormalities. Our findings support the concept that mTLE is a more diffuse process than the hippocampal structural abnormality, which may impact surgical outcome.