The attenuation of experimental autoimmune encephalomyelitis (EAE) by Lovastatin (LOV) has now been well established. The present study was designed to explore the global effect of LOV treatment on expression of immune-related genes in lumbar spinal cord (LSC) during acute EAE by using Affymetrix DNA microarrays. LOV treatment demonstrated the limited infiltration of inflammatory cells into the LSC, and microarray analysis further validated those interpretations by demonstrating relatively less alteration in expression of immune response genes in LOV-treated EAE rats on peak clinical day and recovery vs. untreated EAE counterparts. There was significant change in expression of about 158 immune-related genes (including 127 genes reported earlier) in LOV-treated vs. untreated EAE (>1.5 or <-1.5 fold change; P ≤ .05), of which 140 genes were suppressed and only 18 genes were up-regulated. These altered genes encode for leukocyte-specific markers and receptors, histocompatibility complex, cytokines/receptors, chemokines/receptors, adhesion molecules, components of the complement cascade, cellular activation, and transcription factors and signal transduction-related molecules. Interestingly, TH2 phenotype cytokines such as interleukin-4, interleukin-10, and transforming growth factor-β1 and transcription factors such as peroxisome proliferator-activated receptor (PPAR)-γ were up-regulated in LSC by LOV treatment as further revealed by real-time PCR and immunoblotting. These findings indicate that PPARs may be mediating the antiinflammatory and immunomodulatory effects of LOV. Together, these findings provide new insight into the molecular events associated with the protection provided by statins during treatment of demyelinating diseases such as multiple sclerosis. © 2004 Wiley-Liss, Inc.