It is now well documented that experimental autoimmune encephalomyeltitis (EAE) can be effectively prevented by estrogen therapy. Previously, we identified a limited set of genes that were altered in spleens of mice protected from EAE by 17-estradiol (E2) treatment. As a continuation of these studies, we here present transcriptional changes in genes expressed in spinal cord tissue. The Affymetrix microarray system was used to screen more than 12,000 genes from E2-treated double Tg (BV8S2 and AV4) female mice protected from EAE vs. control mice with severe EAE. We found that estrogen therapy had a profound inhibitory effect on expression of many immune-related genes in spinal cords. Estrogen significantly affected transcription of 315 genes, 302 that were down-regulated and only 13 that were up-regulated by >2.4 fold. A number of genes encoding the histocompatibility complex, cytokines/receptors, chemokines, adhesion molecules, and signal transduction proteins, were strongly down regulated (>20 fold) in estrogen treated mice to levels similar to spinal cord tissue from unmanipulated mice. The identification of genes with altered expression patterns in spinal cords of estrogen treated mice provides unique insight into the process that ultimately results in protection against EAE.