Vitamin D receptor (VDR) participates in multiple immune functions. Here, we determined whether VDR gene-sequence variations are associated with intersubject differences in the risk of acquiring human immunodeficiency virus type 1 (HIV-1) infection. We assessed this in 460 males exposed to HIV-1 by injection drug use (335 infected and 125 uninfected) and 124 seronegative healthy subjects. Multilocus logistic regression analysis revealed haplotypes for rs11568820, rs4516035, rs10735810, rs1544410, and rs17878969 polymorphisms showing association with protection to HIV-1 infection (odds ratio, 0.4 [95% confidence interval, 0.22-0.72]; P = .0025), which remained significant after correction for multiple testing. We infer that VDR haplotypes might influence the risk of HIV-1 acquisition.