Given the presence of DC-SIGN in the placenta and its known interaction with HIV-1, we hypothesized that polymorphism affecting its expression or function might influence the risk of MTCT of HIV-1. Here, we report significant associations between DC-SIGN genetic variants that modulate DC-SIGN expression in placental macrophages, promote HIV-1 capture and transmission to T cells and increase risk of MTCT among Zimbabwean infants.