Anti-IgLON5 is a rare neurological disorder characterized by brainstem dysfunction, abnormal movements, sleep alterations, autoantibodies against IgLON5, and neurodegeneration, sometimes with neuronal deposits of tau. IgLON5 is a neural cell adhesion molecule of unknown function. This study was aimed to determine the effects of loss of function of IgLON5 in a Knockout (IgLON5-KO) mouse model assessing brain morphology, social behavior, and symptoms.IgLON5-KO mouse was produced by CRISPR-Cas9 technology. Two-month-old IgLON5-KO and wild-type mice were subjected to a comprehensive battery of behavioral tests examining locomotion, memory, anxiety, social interaction, and depressive-like behavior. Immunohistochemistry on fixed sagittal brain sections and Western blot brain lysates were used to determine IgLON5 expression. Brain tissue was analyzed for morphological changes and presence of hyperphosphorylated tau.IgLON5-KO mice showed subtle alteration in motor coordination and balance. Female, but not male IgLON5-KO mice exhibited motor hyperactivity, whereas male, but not female IgLON5-KO mice showed depressive-like behavior and excessive nest-building activity. Neuropathological studies demonstrated normal brain morphology and absence of hyperphosphorylated tau.The phenotype of IgLON5-KO mice is different from that expected from patients with anti-IgLON5 disease. IgLON5-KO mice show subtle alterations in motor coordination and balance. Behavioral changes are sex-dependent (females, exhibit hyperactivity; males, depressive-like behavior).