Immunological derangement is assumed to be present in a subgroup of patients affected by drug-resistant epilepsy with serum harboring anti-glutamic acid decarboxylase autoantibodies (GAD-Ab). To further investigate the specific reactivity of GAD-Ab with target cells, we tested sera from drug-resistant epileptics harboring GAD-Ab on cultured fetal rat hippocampal neurons. As a control, we tested sera from GAD-Ab-negative epileptics and GAD-Ab-positive patients affected by Stiff Person Syndrome (SPS), ataxia or diabetes. A specific pattern of reactivity, varying according to disease, was detected on application of sera from GAD-Ab-positive patients with epilepsy, SPS and ataxia, but no specific labeling was found on application of sera from patients with GAD-Ab-negative epilepsy or from GAD-Ab-positive diabetic controls.