To investigate postoperative changes in the cerebral glucose metabolism of patients with mesial temporal lobe epilepsy (MTLE), statistical parametric mapping (SPM) analysis was performed on pre- and postoperative (18)F-fluorodeoxyglucose PET (FDG-PET) images. We included 28 patients with MTLE who had undergone surgery and had been seizure-free postoperatively (16 had left MTLE and 12 right MTLE). All patients showed hippocampal sclerosis by pathology or brain MRI. FDG-PET images of the 12 right temporal lobe epilepsy patients were reversed to lateralize the epileptogenic zone to the left side in all patients. Application of the paired t-test in SPM to pre- and postoperative FDG-PETs showed that postoperative glucose metabolism decreased in the caudate nucleus, the pulvinar of the thalamus, fusiform gyrus, lingual gyrus and the posterior region of the insular cortex in the hemisphere ipsilateral to resection, whereas postoperative glucose metabolism increased in the anterior region of the insular cortex, temporal stem white matter, midbrain, inferior precentral gyrus, anterior cingulate gyrus and supramarginal gyrus in the hemisphere ipsilateral to resection. No significant postsurgical changes in cerebral glucose metabolism occurred in the contralateral hemisphere. Subtraction between pre- and postoperative FDG-PET images in individual patients produced similar findings to the SPM results, and additionally showed that postoperative glucose metabolism increased in the anterior thalamus in 12/28 patients (42.8%). SISCOM (subtraction ictal-interictal SPECT co-registered to MRI) performed in 17 patients showed ictal hyperperfusion in the ipsilateral temporal lobe, including the temporal stem white matter, midbrain, insular cortex and cingulate gyrus, bilateral basal ganglia and thalami, and multiple small regions in the frontoparietal lobes during seizures. This study suggests that brain regions showing a postoperative increase in glucose metabolism appear to represent the propagation pathways of ictal and interictal epileptic discharges in MTLE, whereas the postoperative decrease in glucose metabolism may be related to a permanent loss of afferents from resected anterior-mesial temporal structures.