Caveolin 1 (CAV1) is a component of the myelin sheath and the expression of the gene encoding this protein is increased during myelination in Schwann cells and oligodendrocytes. We sought to investigate the homozygote haplotype compartment in a recently identified polymorphic purine complex at the upstream region of the human CAV1 gene in multiple sclerosis (MS). In a case/control study design, the region was characterized in 126 cases of MS diagnosed based on the Revised McDonald diagnostic criteria, and 460 controls. We report a skew in the homozygote haplotype compartment in the cases versus controls both in a qualitative and quantitative respect. Excess homozygosity for haplotypes was observed in the MS cases (corrected p<0.012, OR=2.54, CI 1.14-5.64). Furthermore, we observed eight homozygote haplotypes in the MS cases that were non-existent in the controls (p<0.0003, OR=20.27, CI 2.50-163.8). For the first time, our data highlight the CAV1 upstream purine complex as a novel susceptibility genomic locus in the pathophysiology of MS. Of utmost importance, the region has been conserved across species, including mouse, guinea pig, rhesus macaque, and human. The functional effect of this region remains to be clarified in the future studies.