Objectives: To assess the association of established multiple sclerosis (MS) risk variants in 3,254 African Americans (1,162 cases and 2,092 controls). Methods: Human leukocyte antigen (HLA)-DRB1, HLA-DQB1, and HLA-A alleles were typed by molecular techniques. Single nucleotide polymorphism (SNP) genotyping was conducted for 76 MS-associated SNPs and 52 ancestry informative marker SNPs selected throughout the genome. Self-declared ancestry was refined by principal component analysis of the ancestry informative marker SNPs. An ancestry-adjusted multivariate model was applied to assess genetic associations. Results: The following major histocompatibility complex risk alleles were replicated: HLADRB1 15:01 (odds ratio [OR] 5 2.02 [95% confidence interval: 1.54-2.63], p 5 2.50e-07), HLA-DRB1 03:01 (OR 5 1.58 [1.29-1.94], p 5 1.11e-05), as well as HLA-DRB1 04:05 (OR 5 2.35 [1.26-4.37], p 5 0.007) and the African-specific risk allele of HLA-DRB1 15:03 (OR 5 1.26 [1.05-1.51], p 5 0.012). The protective association of HLA-A02:01 was confirmed (OR 5 0.72 [0.55-0.93], p 5 0.013). None of the HLA-DQB1 alleles were associated with MS. Using a significance threshold of p , 0.01, outside the major histocompatibility complex region, 8MS SNPs were also found to be associated with MS in African Americans. Conclusion: MS genetic risk in African Americans only partially overlaps with that of Europeans and could explain the difference of MS prevalence between populations. © 2013 American Academy of Neurology.