Experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease of the CNS, which has long been used as an animal model for human multiple sclerosis. Development of autoimmune disease requires coordinated expression of a number of genes that are involved in the activation and effector functions of inflammatory cells. These include genes that encode costimulatory molecules, cytokines, chemokines, and adhesion molecules. Activation of these genes is regulated at the transcriptional level by several families of transcription factors. One of these is the NF-κB family, which is present in a variety of cell types and becomes highly activated at sites of inflammation. To test the roles of NF-κB in the development of autoimmune diseases, we studied EAE in mice deficient in one of the NF-κB isoforms, ie, NF-κB1 (p50). We found that NF-κB1-deficient mice were significantly resistant to EAE induced by myelin oligodendrocyte glycoprotein. The resistance was primarily evidenced by a decrease in disease incidence, clinical score, and the degree of CNS inflammation. Furthermore, we established that the resistance to EAE in NF-κB1-deficient mice was associated with a deficiency of myelin oligodendrocyte glycoprotein-specific T cells to differentiate into either Th1-or Th2-type effector cells in vivo. These results strongly suggest that NF-κB1 plays crucial roles in the activation and differentiation of autoreactive T cells in vivo and that blocking NF-κB function can be an effective means to prevent autoimmune encephalomyelitis.