Autoantibodies against contactin-associated protein-like 2 (CASPR2) are observed in several neurological syndromes, including neuromyotonia (NMT), Morvan syndrome (MoS), and limbic encephalitis. To characterize the clinical and biological presentations of patients with anti-CASPR2 antibodies in the cerebrospinal fluid (CSF). We conducted a retrospective cohort analysis of 18 patients who had anti-CASPR2 antibodies in their CSF between March 2009 and November 2015 at the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques in Lyon, France. Additionally, we analyzed 15 patients who were diagnosed as having NMT or MoS as a comparative group. Clinical presentations, anti-CASPR2 antibodies specificities, brain magnetic resonance imaging, and CSF analyses, cancer prevalence, and evolution. In this cohort of 18 patients with anti-CASPR2 antibodies in their CSF, 17 (94.4%) were male and had a median (range) age of 64.5 (53-75) years; in the second group, 9 of 15 patients (60.0%) with NMT or MoS were male and had a median (range) age of 51 years (1 month to 75 years). Only 3 patients (16.7%) in this cohort had a previous or concomitant history of cancer (prostate, hematological, or thyroid), whereas 9 patients (60.0%) in the second group had a malignant thymoma. Symptoms of limbic encephalitis were observed in all patients, including temporal lobe seizures in 16 patients (88.9%) and memory disorders in 17 patients (94.4%) from the cohort. Extralimbic signs were also evident in 12 of 18 patients (66.7%), including cerebellar ataxia in 6 patients (33.3%). Only 2 patients (11.1%) from the cohort were diagnosed as having NMT. Brain magnetic resonance imaging displayed T2-weighted temporolimbic abnormalities in 14 of 15 patients (93.3%) in the second group. Cerebrospinal fluid analysis was abnormal in 9 of 12 patients (75.0%). For 16 of 18 patients (88.9%), follow-up was performed for at least a 6-month period (median [range], 34 [11-114] months). Of these, 15 (93.8%) improved and 6 (37.5%) relapsed. In all patients in this cohort, IgG4 autoantibodies were detected in the CSF. Anti-CASPR2 antibodies in the CSF targeted the laminin G1 and discoidin domains of CASPR2 in all patients. Importantly, anti-CASPR2 antibodies were detected in the serum but not in the CSF of all patients with NMT or MoS. In this cohort study, anti-CASPR2 antibodies in the CSF are associated with a subtype of autoimmune encephalitis with prominent limbic involvement and seizures that is rarely associated with cancer. Conversely, patients with NMT and MoS have anti-CASPR2 antibodies only in the serum but not in the CSF and frequently present with a malignant thymoma. The anti-CASPR2 antibodies found in these patients targeted the discoidin and laminin G1 domains of CASPR2 and always included IgG4 autoantibodies.