Background: Multiple sclerosis outcome may be influenced by ultraviolet radiation and vitamin D synthesis, suggesting skin type and genes determining this phenotype are candidates for disability. However, though associations between melanocortin 1 receptor (MC1R) single nucleotide polymorphisms and disability are reported, some data are incompatible with their expected influence on skin type. Objective: Determine which MC1R single nucleotide polymorphisms affect disability and establish if ultraviolet radiation modifies such associations. Methods: We studied using linear regression in 525 cases, associations of the Multiple Sclerosis Severity Score (MSSS) with skin type, gender, ultraviolet radiation exposure and six MC1R single nucleotide polymorphisms (rs1805005, rs1805006, rs2228479, rs1805007, rs1805008, rs1805009). Results: CG²⁹⁴ with GG²⁹⁴ genotypes (rs1805009) (coefficient = —1.44, 95% CI —2.30, —0.59, mean MSSS ± SD = 4.33 ± 2.87) and AC⁸⁴ (rs1805006) (coefficient = 1.62, 95% CI 0.17, 3.06, mean MSSS = 7.62 ± 2.43) were associated with MSSS. Associations with Asp294His were found in those with skin types 1/2 and 3/4, and cases stratified by ultraviolet radiation exposure. However, they were seen only in cases with a history of childhood sunburn and not in those without sunburn. We found no significant associations between exposure parameters and MSSS. Conclusions: Multiple Sclerosis outcome is influenced by interactions between host response to ultraviolet radiation and MC1R single nucleotide polymorphisms. The influence of the single nucleotide polymorphisms appears distinct from their association with skin type.