Experimental autoimmune encephalomyelitis (EAE) is induced by immunization with myelin components including myelin oligodendrocyte glycoprotein (MOG). Myelin‐specific Th1 cells enter the central nervous system (CNS) via binding of very late antigen 4 (VLA‐4) to the endothelial vascular cell adhesion molecule 1 (VCAM‐1). In the present study, mice with a homologous disruption of the gene encoding IL‐6 are found to be resistant to MOG‐induced EAE as evidenced by absence of clinical symptoms, minimal infiltration of CD3⁺ T cells and monocytes into the CNS and lack of demyelination. The failure to induce EAE in IL‐6^{− / −} mice is not due to the absence of priming, since lymphocytes of immunized IL‐6^{− / −} mice proliferate in response to MOG and produce pro‐inflammatory cytokines including IL‐2 and IFN‐γ. However, in MOG‐immunized IL‐6^{− / −} mice, serum anti‐MOG antibody titers were found to be drastically reduced. This observation is unlikely to be responsible for resistance to EAE, because B cell‐deficient (μMT) mice proved to be fully susceptible to the disease. A striking difference between MOG‐immunized wild‐type (wt) and IL‐6^{− / −} mice was the expression of endothelial VCAM‐1 and ICAM‐1, which were dramatically up‐regulated in the CNS in wt but not in IL‐6^{− / −} mice. Taking into account recent studies on the role of VCAM‐1 in the entry of Th1 cells into the CNS, the absence of VCAM‐1 on endothelial cells in IL‐6^{− / −} mice may explain their resistance to EAE.