We performed a molecular epidemiology study in a population of 105 mesial temporal lobe epilepsy with hippocampal sclerosis (MTE-HS) patients in order to investigate the role of a polymorphism in the serotonin transporter gene (SLC6A4) in the prediction of antiepileptic drug (AED) treatment response. Homozygous carriers of the 12-repeat allele had an almost fourfold increase in risk for a MTE-HS not responding to medical treatment (OR 3.88; CI 95% 1.40-10.7; p=0.006) compared to carriers of the 10-repeat allele. Therefore, a polymorphism of SLC6A4 might be a genetic marker of pharmacoresistance in MTE-HS patients.