Objective: To determine the H-1 MRS findings in patients with intractable temporal lobe epilepsy (TLE) who had no detectable abnormality on either qualitative or quantitative MRI. Background: Previous work has indicated that similar to 20% of patients with TLE remain MRI negative after extensive qualitative and quantitative investigation. Single-voxel H-1 MRS provides a means of identifying potentially diffuse disease. Methods: Seven patients with intractable TLE, normal routine MRI, normal hippocampal volumes, and normal hippocampal and amygdala quantitative T2 values underwent single-voxel H-1 MRS of the medial temporal lobes. The results are compared with those from 13 control subjects and 15 patients with evidence of hippocampal sclerosis (HS). Results: The ratio N-acetylaspartate/(choline-creatine + phosphocreatine) was abnormally low in five of the seven MRI-negative patients. In two of these patients, the ratios were low bilaterally. The observed MRS ratios in the MRI-negative group with abnormal EEG were similar to those from temporal lobes ipsilateral to HS, suggesting the presence of widespread or diffuse disease of a similar degree in both groups. Conclusions: These results demonstrate that MRS can provide evidence of temporal lobe abnormalities in TLE patients who show no abnormality on extensive MRI investigation.