The present study reports promoter variants in four sub-Saharan African populations that may affect BST-2 gene regulation. Recently, an in/del within the BST-2 promoter has been associated with HIV-1 disease progression in a Spanish cohort. Hence, we sequenced the proximal promoter region of the BST-2 gene in 581 individuals from South Africa, Zimbabwe, Malawi, and Cameroon. Seven SNPs were identified: rs28413176 (+26i6/Δ6); rs28413175 (-160i1/Δ1), -187A>G (nucleotide position -17516614); rs28413174 (-193G>A); rs73921425 (-199G>A); rs12609479 (-201C>T); and rs112492472 (-225C>T). The -199A and -225T alleles showed interesting trends across the sub-Saharan continent. Using predictive bioinformatics tools, we show that allelic variation at -199 and -201 potentially affect key transcription factor binding sites including bHLH, c-Myb, and E47. Importantly, data available from the ENCODE study gave further credence to our hypothesis of transcriptional regulation of BST-2 by a bHLH TF such as Mxi1. The possible repressive transcriptional effect of Mxi1 combined with the allelic frequency trend seen at -199 between African populations overlays well with current HIV-1 prevalence data, and may be a contributing factor to this phenomenon. The differences in HIV-1 prevalence in African countries could be, in part, due to distribution of genetic variants that affect susceptibility to HIV-1. Our findings therefore have substantive value for the design of future diagnostics for global health oriented diagnostics for HIV-1 susceptibility, and rational therapeutics on the critical path to personalized medicine in the African continent. As HIV-1 epidemiology vastly impacts human populations around the world, the population genomics strategy we have utilized herein can have value for other global regions as well.