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Inflammation plays a role in the pathogenesis of immune‐mediated epilepsy, but also in epilepsy of other etiology such as hippocampal sclerosis. This study aimed to characterize immune cell signatures in the peripheral blood (PB) and cerebrospinal fluid (CSF) in temporal lobe epilepsy (TLE) of different etiologies. We retrospectively evaluated CSF routine parameters and immune cell profiles using flow cytometry in a cohort of 51 patients and 45 age‐matched controls with functional disorders. Groups were comprised of patients with nonlesional TLE (n = 26), TLE due to hippocampal sclerosis (n = 14), or limbic encephalitis with antibodies against the 65‐kDa isoform of glutamic acid decarboxylase (GAD65‐LE; n = 11). TLE patients showed increased proportions of human leukocyte antigen–DR isotype (HLA‐DR)‐expressing CD4+ T lymphocytes in the CSF. Furthermore, they were characterized by a shift in monocyte subsets toward immature CD14lowCD16+ cells in the PB and blood/CSF‐barrier dysfunction. Whereas TLE patients in general showed similar immune cell profiles, patients with GAD65‐LE differed from other TLE patients by increased proportions of HLA‐DR–expressing CD8+ T lymphocytes and type 2/3 oligoclonal bands. These findings point to a role of innate and adaptive immunity in TLE. CSF parameters may help to discriminate epilepsy patients from controls and different forms of TLE from each other. [ABSTRACT FROM AUTHOR]