Multiple sclerosis (MS) risk is determined by environment and genes. The authors investigated in 419 cases and 422 controls if polymorphism in the vitamin D receptor (VDR), melanocortin-1 receptor (MC1R), and tyrosinase (TYR) genes is linked with MS risk and outcome. VDR ff was associated with reduced (odds ratio [OR] = 0.59) and MC1R His294-encoding alleles with increased (OR = 2.21) risk. MC1R Glu84/Glu84 was linked with disability (OR = 5.65). These preliminary data suggest a role for these genes in MS pathogenesis.