Interleukin (IL)-6 is crucial for the induction of many murine models of autoimmunity including experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. While IL-6-deficient mice (IL-6 KO) are resistant to EAE, we showed previously that in transgenic mice with astrocyte-targeted production of IL-6-restricted to the cerebellum (GFAP-IL6), EAE induced with MOG(35-55) was redirected away from the spinal cord to the cerebellum. To further establish the importance of IL-6 produced in the central nervous system, we have generated mice producing IL-6 essentially only in the brain by crossing the GFAP-IL6 mice with IL-6 KO mice. Interestingly, GFAP-IL6-IL-6 KO mice showed a milder but almost identical phenotype as the GFAP-IL6 mice, which correlated with a lower load of inflammatory cells and decreased microglial reactivity. These results indicate that not only is cerebellar IL-6 production and eventual leakage into the peripheral compartment the dominating factor controlling this type of EAE but that it can also facilitate induction of autoimmunity in the absence of normal systemic IL-6 production. © 2013 Wiley Periodicals, Inc.