Inhibitors of apoptosis (IAPs) modulate cell death and play critical role in signal transduction that promotes inflammation. Recently, Smac mimetics, which are IAP antagonists, have attracted attention as novel cancer therapeutics. Cellular Inhibitor of Apoptosis 2 (cIAP2), a member of IAP family, positively affects both NF-κB and MAPK activation in response to many inflammatory stimuli. We observed that the lack of cIAP2 ablates LPS-induced neuroinflammation. Also, cIAP2-/- macrophages demonstrated diminished antigen presentation potential that could contribute to ablated immunity. In addition to these functions, we have previously reported that cIAP2 also regulates the activation of Interferon Regulatory Factor 1 (IRF1). Since IRF1-/- mice are resistant to experimental autoimmune encephalomyelitis (EAE), we hypothesized that cIAP2-/- mice will be protected from the disease. Surprisingly, induction of EAE in cIAP2-/- mice resulted in exaggerated infiltration of immune cells increased expression of proinflammatory cytokines and demyelination within CNS. We found that the lack of cIAP2 induces caspase-8 expression in microglia derived macrophages, contributing to their activation and polarization towards M1 phenotype, and exacerbates the symptoms of EAE. These findings suggest that cIAP2 limits neuroinflammation in the CNS and thus the use of Smac mimetics as chemotherapeutics needs to be reevaluated.