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The bone marrow stromal cell antigen 2 (BST2) gene encodes a host restriction factor that acts as an innate immune sensor of HIV-1 exposure and suppresses release of HIV-1 particles. We aimed to identify associations of variants in the BST2 gene region with HIV-1 acquisition and disease progression.Using HIV+ cases and HIV− controls from the Urban Health Study (n = 3136 African Americans and European Americans who inject drugs), we tested 470 variants in BST2 and its flanking regions for association with HIV-1 acquisition and log-transformed viral load.We found that the single nucleotide polymorphism (SNP) rs113189798 surpassed the P value threshold corrected for multiple testing. The rs113189798-G allele (frequency = 16% in African Americans, 4% in European Americans) was associated with increased HIV-1 acquisition risk (meta-analysis P = 1.43 × 10−4): odds ratio (95% confidence interval) of 1.22 (1.01–1.49) in African Americans and 2.17 (1.43–3.33) in European Americans. We also found that the previously reported rs12609479-A allele (frequency = 35% in African Americans, 81% in European Americans) was nominally associated with decreased risk of acquiring HIV-1 in our study (meta-analysis P = 0.036). Rs12609479-A is predicted to increase BST2 expression and thereby decrease risk of acquiring HIV-1. Rs113189798 and rs12609479 were only weakly correlated [square of the correlation coefficient (r2) = 0.2–0.4] and represented distinct association signals. None of our tested variants were significantly associated with log-transformed viral load among the HIV-infected cases.Our findings support BST2 as a genetic susceptibility factor for HIV-1 acquisition: identifying a novel SNP association for rs13189798 and linking the previously reported regulatory SNP rs12609479 to HIV-1 acquisition.