We have analyzed a CA repeat polymorphism localized 46-kb upstream of the Fas ligand gene in Spanish and American populations that include 139 healthy controls and a cohort of 177 unrelated relapsing and remitting multiple sclerosis (MS) patients. The MS patients consisted of two groups, one with a family history of MS and one without. The frequency of the 13 CA repeats (allele B) was lower (p=0.01) in MS patients than in controls, 0.45 and 0.55 respectively. The odds ratio (BB vs. AB/AA) for MS patients vs. healthy controls was 0.51 (95% CI 0.3-0.9; p=0.01). The odds ratio (BB vs. AB/AA) for MS patients extracted from multiply affected families vs. healthy controls was 0.22 (95% CI 0.07-0.62; p=0.002). The HLA DRB1*1501-DQB1*0602 haplotype is associated with B allele with a relative frequency higher than A allele (0.52 and 0.48 in patients vs. 0.68 and 0.32 in controls). The results suggest that chromosomes with B allele have a genetic background that reduces susceptibility to MS, particularly in the familial forms.