The functional changes that occur throughout the human brain after the selective removal of an epileptogenic lesion remain unclear. Subtemporal selective amygdalohippocampectomy (SAH) has been advocated as a minimally invasive surgical procedure for patients with medically intractable mesial temporal lobe epilepsy (MTLE). We evaluated the effects of subtemporal SAH on cerebral glucose metabolism and memory function in 15 patients with medically intractable MTLE with hippocampal sclerosis using [(18)F]-fluorodeoxyglucose PET (FDG-PET) and the Wechsler Memory Scale-Revised. The patients were evaluated before and 1-5 years (mean 2.6 years) after surgery. In patients with MTLE of the language-dominant hemisphere, the basal temporal language area was preserved by this surgical approach. Voxel-wise comparison of FDG-PET images was conducted using SPM5 to identify the brain regions showing postoperative changes in glucose metabolism (height threshold, P = 0.01 corrected for multiple comparisons; extent threshold, 100 voxels). During spatial normalization of the postoperative FDG-PET images, we used cost-function masking to minimize any inappropriate image distortion as a result of the abnormal signal within the surgically resected region. Postoperative glucose metabolism increased in extratemporal areas ipsilateral to the affected side, such as the dorsolateral prefrontal cortex, and the dorsomedial and ventromedial frontal cortices. Glucose metabolism also increased in the bilateral inferior parietal lobules and in the remaining temporal lobe regions remote from the resected mesial temporal region, such as the superior temporal gyrus and the temporal pole. By contrast, postoperative glucose metabolism decreased only in the mesial temporal area adjacent to the resected region. Postoperative verbal memory, delayed recall and attention/concentration scores were significantly better than preoperative scores regardless of the resected side. This study suggests that the selective removal of the epileptogenic region in MTLE using a subtemporal approach improved cerebral glucose metabolism in the areas receiving projections from the affected mesial temporal lobe. Cognitive improvement might result from a combination of good seizure control and minimizing the regions of the brain with postoperative functional impairment.