Abstract Objective The risk of multiple sclerosis (MS) is influenced by HLA-DRB1, while protective effects have been proposed for HLA-A*02 and HLA-C*05 . Our aim was to further understand the role of HLA class I in MS through a comprehensive investigation. Methods 1529 MS patients and 1814 controls from Sweden and Norway were genotyped for HLA-DRB1 , HLA-A , and HLA-C . Simultaneous analysis of all alleles while adjusting for confounding was achieved using logistic regression. Results We observed independent effects of all three genes. We confirm the HLA-A*02 (OR = 0.73, p = 9.2 × 10 − 4 ) association and report a novel effect of HLA-C*08 (OR = 1.85, p = 0.0093). Conclusions The HLA class I region contains two factors modulating MS risk, characterized by independent associations with HLA-A and HLA-C.