There are overwhelming data supporting the inflammatory origin of some epilepsies (e.g., Rasmussen's encephalitis and limbic encephalitis). Inflammatory epilepsies with an autoimmune component are characterized by autoantibodies against membrane-bound, intracellular or secreted proteins (e.g., voltage gated potassium channels). Comparably, little is known regarding autoantibodies targeting nuclear antigen. We tested the hypothesis that in addition to known epilepsy-related autoantigens, the human brain tissue and serum from patients with epilepsy contain autoantibodies recognizing nuclear targets. We also determined the specific nuclear proteins acting as autoantigen in patients with epilepsy. Brain tissue samples were obtained from patients undergoing brain resections to treat refractory seizures, from the brain with arteriovenous malformations or from post-mortem multiple sclerosis brain. Patients with epilepsy had no known history of autoimmune disease and were not diagnosed with autoimmune epilepsy. Tissue was processed for immunohistochemical staining. We also obtained subcellular fractions to extract intracellular IgGs. After separating nuclear antibody-antigen complexes, the purified autoantigen was analyzed by mass spectrometry. Western blots using autoantigen or total histones were probed to detect the presence of antinuclear antibodies in the serum of patients with epilepsy. Additionally, HEp-2 assays and antinuclear antibody ELISA were used to detect the staining pattern and specific presence of antinuclear antibodies in the serum of patients with epilepsy. Brain regions from patients with epilepsy characterized by blood-brain barrier disruption (visualized by extravasated albumin) contained extravasated IgGs. Intracellular antibodies were found in epilepsy (n=13/13) but not in multiple sclerosis brain (n=4/4). In the brain from patients with epilepsy, neurons displayed higher levels of nuclear IgGs compared to glia. IgG colocalized with extravasated albumin. All subcellular fractions from brain resections of patients with epilepsy contained extravasated IgGs (n=10/10), but epileptogenic cortex, where seizures originated from, displayed the highest levels of chromatin-bound IgGs. In the nuclear IgG pool, anti-histone autoantibodies were identified by two independent immunodetection methods. HEp-2 assay and ELISA confirmed the presence of anti-histone (n=5/8) and anti-chromatin antibodies in the serum from patients with epilepsy. We developed a multi-step approach to unmask autoantigens in the brain and sera of patients with epilepsy. This approach revealed antigen-bound antinuclear antibodies in neurons and free antinuclear IgGs in the serum of patients with epilepsy. Conditions with blood-brain barrier disruption but not seizures, were characterized by extravasated but not chromatin-bound IgGs. Our results show that the pool of intracellular IgG in the brain of patients with epilepsy consists of nucleus-specific autoantibodies targeting chromatin and histones. Seizures may be the trigger of neuronal uptake of antinuclear antibodies.