We investigated the role of the KIR loci and their HLA class I ligands in a large cohort of African American MS patients (N=907) and controls (N=1456). No significant differences in carrier frequencies for any KIR locus or haplotype were observed between cases and controls. However, examination of KIR in the context of their cognate HLA ligands revealed a strong protective effect for KIR3DL1 in combination with HLA-A and-B alleles bearing the Bw4 motif (p=10[−8] ; OR=0.60, CI=0.50-0.71) and the Bw4 ligand alone (Table 3; p<10[−6] ; OR=0.63, CI=0.53-0.75). The observed effect cannot be explained by either a specific HLA-B allele or by linkage disequilibrium with HLA-DRB1 or HLA-A. The protective effect was observed only in individuals who were not positive for the MS risk allele HLA-DRB1*15:01 (p<10[−6] ; OR=0.61, CI=0.51-0.74). Our study, the first investigation of KIR and MS in African Americans, confirms and refines previous findings in a European cohort.