An interferon λ4 gene (IFNL4) knockout allele (rs368234815; TT) is associated with spontaneous and IFN-α-dependent cure of hepatitis C virus infection. The role of this polymorphism in the susceptibility to human immunodeficiency virus type 1 (HIV-1) infection is controversial. This study aimed to assess the association of this knockout IFNL4 variant and sexually transmitted HIV-1 infection. A total of 228 HIV-1-positive individuals and 136 HIV-exposed seronegative individuals were investigated for their association with IFNL4 rs368234815 genotypes. The IFNL4 ΔG functional allele is associated with increased susceptibility to HIV-1 infection through the sexual route (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.2-3.6; P = .004). A meta-analysis including a population of injection drug users suggests a codominant mode of inheritance of this risk factor (OR, 2.0; 95% CI, 1.3-3.2; P = .001).