Experimental data in animals show that 5-HT(1A) receptors are predominantly located in limbic areas and suggest that serotonin, via these receptors, mediates an antiepileptic and anticonvulsant effect. In this PET study, we used an antagonist of the 5-HT(1A) receptor, [(18)F]MPPF, to assess the extent of 5-HT(1A) receptor binding changes in a group of seven temporal lobe epilepsy (TLE) patients with hippocampal ictal onset demonstrated by intracerebral EEG recording. On the basis of MRI-measured hippocampal volumes (HV), patients were classified into "normal HV" or "hippocampal atrophy" (HA). Voxel-based analyses (SPM99) were performed to objectively assess the differences in [(18)F]MPPF binding potential (BP) between patients (taken as a group or as individuals) and a database of 48 controls subjects. In the full group of patients, a significant decreased BP was detected ipsilateral to the epileptogenic zone in the hippocampus, temporal pole, insula, and temporal neocortex. This result was confirmed in the subgroup of patients with HA. In patients with normal HV, the BP decrease was restricted to the temporal pole. TLE patients also demonstrated an increased BP in various regions contralateral to the epileptogenic zone. These data suggest that in TLE patients with hippocampal seizure onset, the decrease in 5-HT(1A) receptor binding partly reflects hippocampal neuronal loss, but is also observed in various regions involved in temporo-limbic epileptogenic networks that appeared normal on MRI. Further studies are warranted to evaluate the clinical usefulness of [(18)F]MPPF-PET as compared to other established PET tracers in drug resistant TLE.