Genome-wide association studies have revealed a large number of genetic associations with autoimmune diseases. Despite this progress, the mechanisms underlying the contribution of allelic variants to the onset of immune-related diseases remain mostly unknown. Our recent meta-analysis of genome-wide association studies of multiple sclerosis (MS) identified a new susceptibility locus tagged by a single nucleotide polymorphism, rs17824933 (p = 3.8 × 10(-9)), that is found in a block of linkage disequilibrium containing the CD6 gene. Because CD6 plays an important role in maintenance of T cell activation and proliferation, we examined the biologic phenotypes of the risk-associated allele. In this article, we report that the MS susceptibility allele in CD6 is associated with decreased expression of full-length CD6 in CD4(+) and CD8(+) T cells. As a consequence, proliferation is diminished during long-term activation of CD4(+) T cells from subjects with the risk allele. Selective knockdown of full-length CD6 using exon 5-specific small interfering RNA induces a similar proliferation defect of CD4(+) T cells from subjects homozygous for the protective allele. Exon 5 encodes for the extracellular binding site of the CD6 ligand ALCAM, which is required for CD6 stimulation. In CD4(+) T cells from subjects with the risk allele, exon 5 is consistently underexpressed, thereby providing a mechanism by which the allele affects proliferation of CD4(+) T cells. These findings indicate that the MS risk allele in the CD6 locus is associated with altered proliferation of CD4(+) T cells and demonstrate the influence of a disease-related allelic variant on important immunological characteristics.