We have undertaken a test-re-test [11C]flumazenil (FMZ) PET study in 10 drug-resistant epileptic patients, including six with a mesiotemporal epilepsy (MTE), and 10 normal controls, in order to investigate seizure-related short-term plasticity of benzodiazepine (BZD) receptors. All subjects underwent two FMZ-PET scans at a 1 week interval. Patients benefited from a concurrent video-EEG monitoring which allowed determination of the duration of the interictal period (IP) preceding each PET. Test-re-test whole brain B'(max) variations, evaluated with a partial-saturation injection protocol, were similarly observed in patients and controls, suggesting a physiological modulation of BZD receptors. Five patients (50%), but no controls, also demonstrated clinically significant test-re-test FMZ-PET variations in the mesial temporal region. This was observed in all three patients with MTE and no hippocampal atrophy in whom only the PET study associated with the shortest IP correctly identified the epileptogenic zone. Statistical analysis revealed a significant effect of IP duration on BZD receptor B'(max) in MTE patients, suggesting that the shorter the IP, the lower the B'(max) in the epileptogenic hippocampus. FMZ-PET appears to be an interesting tool for investigating both normal and abnormal short-term modulations of the BZD receptor system, and should ideally be performed within a few days following a seizure in patients with MTE and a normal MRI.