Objective: In a recent genome-wide association study of HIV-1 -infected individuals in the Euro-CHAVI cohort, viral load set-point was strongly associated with genotypes defined by two single nucleotide polymorphisms (SNPs) (rs9264942 and rs2395029) within the human major histocompatibility complex (MHC) region on chromosome 6. We attempted to confirm this finding in African-Americans and to address whether these SNPs are in linkage disequilibrium with human leukocyte antigen (HLA) class I alleles that mediate innate and adaptive immunity. Design: Our analyses relied on 121 African-American adolescents with chronic HIV-1 infection and quarterly immunological and virological outcome measures in the absence of therapy. Methods: PCR-based techniques were used to genotype two SNPs along with HLA class I alleles. Their associations with HIV-1 viral load set-point and longitudinal CD4+ and CD8+CD38+ T cell counts were tested in univariate and multivariable models. Results: The CC genotype at rs9264942 was associated with reduced viral load, but not with immunological outcomes or category of disease control. Consistent associations of favorable virologic outcomes were observed with B*57 (mostly B*5703) but not with rs2395029G allele at the HCP5 locus, which is in absolute linkage disequilibrium with B*5701 (in individuals of European descent), and not B*5703. Conclusion: Although rs9264942 and B*57 (but not rs2395029G) are clearly associated with control of viral load set-point among African-Americans, fine-mapping of MHC SNPs in populations of African and European descent should help reveal the causative variants and the underlying functional mechanisms. © 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.