ABSTRACT Retrospective cohort study to investigate which factors most reliably distinguish incidental GAD65‐antibodies (iGAD65) from true GAD65‐antibody neurological disease (tGAD65). 167 adults with positive serum and CSF GAD65‐antibodies (> 0.02 nmol/L by radioimmunoassay) were classified as tGAD65 or iGAD65, with diagnostic performance of paraclinical parameters compared in discovery and validation cohorts. CSF GAD65‐antibody titers ≥ 1 nmol/L performed best in discovery (AUC 0.956) and validation (AUC 0.949; p = 0.814), with 89.7% sensitivity and 94% specificity for identifying tGAD65. Serum titers > 20 nmol/L and indices of intrathecal synthesis showed lower discriminative ability. Our finding aims to reduce misdiagnosis and identify potential immunotherapy‐responsive diseases.