Introduction: Autoimmune epilepsy is poorly recognized, and its incidence is unknown. Objective: To determine the incidence of neuronal autoantibodies in patients with epilepsy of unknown etiology. Materials and methods: An observational, longitudinal, prospective and analytical study was carried out to evaluate the presence of autoantibodies for autoimmune encephalitis, glutamic acid decarboxylase-65 and onconeuronal antibodies in serum and cerebrospinal fluid in consecutive patients with epilepsy of unknown etiology. Results: A total of 60 patients and 80 controls (30 healthy ones, 30 with multiple sclerosis, 10 with systemic lupus erythematosus, and 10 with Sjögren’s syndrome) were included to detect neuronal antibodies. A total of 28/60 (47%) epilepsy patients had antibodies against N-methyl-D-aspartate receptor, contactin-associated protein 2, leucine-rich glioma-inactivated protein 1 and glutamic aciddecarboxylase, an incidence that was significantly (p < 0.001) higher than that in the combined control cohort. Patients and controls were negative for onconeuronal antibodies, except six cases of epilepsy, one case of multiple sclerosis and three cases of Lupus with positive a-glutamic acid decarboxylase by indirect immunofluorescence tissue-based assay and immunoblotting. No difference was found in the incidence of the autoantibodies studied between male and female patients with epilepsy. The incidence of positive autoantibodies in patients with focal epilepsies was significantly higher than that in patients with generalized epilepsy (p < 0.01). Conclusions: Antibodies against receptors (NMDA receptor), proteins associated with VGKC (LGI1, CASPR2) and antibodies directed at intracellular antigens (GAD65) were found in the serum and cerebrospinal fluid of patients with epilepsy, suggesting an autoimmune etiology.