A subset of patients with COVID-19 display neurologic symptoms but it remains unknown whether SARS-CoV-2 damages the central nervous system (CNS) directly through neuroinvasion, or if neurological symptoms are due to secondary mechanisms, including immune-mediated effects. Here, we examined the immune milieu in the CNS through the analysis of cerebrospinal fluid (CSF) and in circulation through analysis of peripheral blood mononuclear cells (PBMCs) of COVID-19 patients with neurological symptoms. Single cell sequencing with paired repertoire sequencing of PBMCs and CSF cells show evidence for unique immune response to SARS-CoV-2 in the CNS. Strikingly, anti-SARS-CoV-2 antibodies are present in the CSF of all patients studied, but the antibody epitope specificity in the CSF and relative prevalence of B cell receptor sequences markedly differed when compared to those found in paired serum. Finally, using a mouse model of SARS-CoV-2 infection, we demonstrate that localized CNS immune responses occur following viral neuroinvasion, and that the CSF is a faithful surrogate for responses occurring uniquely in the CNS. These results illuminate CNS compartment-specific immune responses to SARS-CoV-2, forming the basis for informed treatment of neurological symptoms associated with COVID-19. ### Competing Interest Statement The authors have declared no competing interest.

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