We tested bone marrow stromal cell antigen 2 (BST-2) gene variants rs3217318, a 19-base-pair insertion/deletion polymorphism in the promoter region, and rs10415893, a tag single-nucleotide polymorphism in the 3′ untranslated region, for their association with human immunodeficiency virus type 1 (HIV-1) infection and disease progression. The study included 356 subjects exposed to HIV-1 (185 with and 171 without infection) and 188 controls. The first decrease in the CD4+ T-cell count to <200 cells/µL was used as the primary outcome, whereas the primary outcome plus initiation of any antiretroviral treatment was used as a secondary composite outcome. Association with progression was found for both rs3217318 and rs10415893, following an overdominant model. Diplotype analysis revealed faster progression to both outcomes for subjects carrying the Δ19_G/i19_A diplotype. Luciferase assay showed that a promoter sequence containing the i19 allele had the lowest expression levels, suggesting that i19 allele carriers could have less BST-2 expression, reducing their capability to retain viral particles. These results point to the relevance of BST-2 as a host genetic factor modifying HIV-1 disease progression.