Technical Abstract: Scrapie is a naturally occurring transmissible spongiform encephalopathy (TSE) that affects sheep and goats. While a change in prion protein conformation has been established as an important aspect of disease, other aspects of TSE pathogenesis are not fully understood. The preset study used protein expression microarrays to determine if cytokine protein levels in the brain and periphery increase during the course of scrapie infection, and if such changes correlated with clinical signs and histopathology. 62 cytokine proteins were screened in the Tg338 murine model of scrapie infection. For most cytokines, the pattern of expression in the brain, spleen, serum and mesenteric lymph node consisted of an increase in expression over control animals at the first time point studies (100 days p.i.), with these levels dipping slightly at the intermediate time point tested (160 days p.i.), only to increase again at the end stage of infection (>190 days p.i.) Four of the 62 cytokines were found to be increased over controls at all points of infection in both the brain and serum: eotaxin-2, IL-4, lymphotactin and SDF-1A. Further statistical analysis was done on these 4 cytokines. The levels of eotaxin and IL-4 were increased in serum and all four cytokines were increased in brain; these changes were significantly greater than the control values at all time points of infection. These 4 cytokines are involved in dendritic cell recruitment and expression, and therefore this information along with the general pattern of cytokine protein expression revealed in all examined tissues could aid in discerning the pathogenesis of scrapie-induced disease and other TSEs. This finding could also be important for future studies aiming to identify antemortem biomarkers for scrapie infection.