Anti-neuronal antibodies that are related with autoimmune encephalitis syndromes may also be found in children with new onset seizures or chronic epilepsy. To unravel the significance of autoimmune astrocytopathy in epilepsy, we investigated serum antibody to glial fibrillary acidic protein (GFAP), another autoantigen described in autoimmune encephalitis with seizures, in 38 children with focal seizures of undetermined cause. GFAP antibody was screened with cell based assay and indirect immunohistochemistry and was found in two boys with normal brain MRI and unrevealing medical history prior to seizures. The 2-year-old boy had chronic treatment-resistant frontal lobe epilepsy. The 2.5-year-old boy had a single episode of focal seizures and remained seizure free thereafter in a follow-up period of 4 years. Nevertheless, he showed severe cognitive and language impairment. These results suggest that autoimmune astrocytopathy may be present in some epilepsy patients. Whether this immune response is a bystander effect generated by seizure-induced astrocytosis or directly involved in epileptogenesis needs to be further studied.