Multiple sclerosis (MS) is a common and severe neurological disorder associated with an autoimmune response directed against myelin components within the CNS. Lymphocyte activation, extravasation, and recruitment, as well as effector function, involves the turning on and off of a number of genes, thus triggering specific transcriptional pathways. The characterization of the transcriptome in MS lesions should provide a better understanding of the mechanisms that generate and sustain the pathogenic immune response in this disease. Here we performed transcriptional profiling of 56 relevant genes in brain specimens from eight MS patients and eight normal controls by kinetic RT-PCR. Results showed a high transcriptional activity for the gene coding for myelin basic protein (MBP); however, it was not differentially expressed in MS samples, suggesting that remyelination is an active process also in the noninflammatory brain. CD4 and HLA-DRα transcripts were dramatically increased in MS as compared with controls. This reveals a robust MHC class II up-regulation and suggests that Ag is being presented locally to activated T cells. Although analysis of cytokine and cytokine receptor genes expression showed predominantly increased levels of several Th1 molecules (TGF-β, RANTES, and macrophage-inflammatory protein (MIP)-1α) in MS samples, some Th2 genes (IL-3, IL-5, and IL-6/IL-6R) were found to be up-regulated as well. Similarly, both proinflammatory type (CCR1, CCR5) and immunomodulatory type (CCR4, CCR8) chemokine receptors were differentially expressed in the MS brain. Overall, our data suggest a complex regulation of the inflammatory response in human autoimmune demyelination.