Microglial activation has been identified as one factor which contributes to the deterioration in function associated with experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. Microglial activation is characterized by an increase in the expression of cell surface markers such as CD40 and an increase in the production of proinflammatory cytokines such as interleukin 1β (IL-1β). Recent evidence has indicated that microglial activation is modulated by the interaction between CD200 which is expressed on neurons and its cognate receptor, CD200 receptor, which is expressed on microglia (Lyons et al., 2007). The objectives of this study were to establish whether any change in microglial activation in the spinal cord of mice with EAE was associated with a downregulation of CD200 and to assess whether similar changes were observed in hippocampus. EAE was induced in C57 mice by injection of myelin oligodrocyte glycoprotein (MOG), pertussis toxin (PT) and complete Freund’s adjuvant (CFA), and 48 hours later by an additional injection of PT. Clinical symptoms were observed over 21 days (Reinke et al., 2007) and symptoms consistent with the onset of EAE were observed after 10 days and these progressed to hindlimb weakness thereafter. At the end of the 21 day period, mice were sacrificed and spinal cord and hippocampus were removed. Tissue was prepared for analysis of CD40 and CD200 mRNA by QPCR and for analysis of pro-inflammatory cytokines by ELISA. We observed an increase in the expression CD40 mRNA in the hippocampus and the spinal cord of mice with EAE compared with control mice (p<0.05, ANOVA, n=6). We further report an increase in IL-1β protein in the hippocampus and spinal cord of mice with EAE mice (p<0.05, ANOVA, n=6). The increase in CD40 mRNA was associated with a decrease in CD200mRNA and protein in the spinal cord of EAE mice (p<0.05, ANOVA, n=6) providing further evidence of an inverse correlation between microglial activation and expression of CD200. The data highlight the importance of the CD200 receptor-ligand interaction in the inflammatory phenotype associated with the symptoms of EAE.