We previously reported that YKL-40, the human analog of mouse breast regression protein 39 ([BRP-39] chitinase 3-like 1), is elevated in the cerebrospinal fluid of patients with a variety of neuroinflamma-tory conditions, such as multiple sclerosis and traumatic brain injury. Expression of YKL-40 in the CNS was predominantly associated with reactive astrocytes in the vicinity of inflammatory lesions. Because previous studies have shown that reactive astrocytes play a critical role in limiting immune infiltration in the mouse model of experimental autoimmune encephalomyelitis, we explored the role of BRP-39 in regulating neuroinflammation in experimental autoimmune encephalomyelitis. Using BRP-39-deficient (BRP-39^−/−) mice, we demonstrate the importance of BRP-39 in modulating the severity of clinical experimental autoimmune encephalomyelitis and CNS neuroinflammation. At disease onset, absence of BRP-39 had little effect on clinical disease or lymphocytic infiltrate, but by 14 days after immunization, differences in clinical scores were evident. By 28 days after immunization, BRP-39^−/− mice showed more severe and persistent clinical disease than BRP-39^+/+ controls. Histopathological evaluation showed that BRP-39^−/− mice had more marked lymphocytic and macrophage infiltrates and gliosis versus BRP-39^+/+ mice. These findings support the role of BRP-39 expression in limiting immune cell infiltration into the CNS and offer a new target to modulate neuroinflammation.