The clinical course and outcome of HIV-1 infection are highly variable among individuals. Interleukin 4 (IL-4) is a key T helper 2 cytokine with various immune-modulating functions including induction of immunoglobulin E (IgE) production in B cells, downregulation of CCR5 and upregulation of CXCR4, the main co-receptors for HIV. Our objective is to investigate whether single-nucleotide polymorphisms (SNPs) in the IL-4 promoter 589 C/T and IL-4 Ralpha I50V affect the susceptibility to HIV infection and its progression to AIDS in North Indian individuals. The study population consisted of 180 HIV-1 seropositive (HSP) stratified on the basis of disease severity (stage I, II, III), 50 HIV-1 exposed seronegative (HES), and 305 HIV-1 seronegative (HSN) individuals. The subjects were genotyped for IL-4 589 C/T promoter polymorphism and IL-4 Ralpha I50V by polymerase chain reaction restriction fragment length polymorphism. The results showed that IL-4 589 C/T was not associated with the risk of HIV infection and disease progression. However, the IL-4Ralpha I50 allele and genotype was significantly increased in HSP compared to HSN and HSP and was associated with risk of HIV infection. The frequency of IL-4Ralpha I50 allele in the HSP group was higher than in HSN (76.11 vs. 64.75%; P = 0.000; OR = 1.734) and HES (76.11% vs. 62.00%; P = 0.007; OR = 1.953). Homozygous IL-4Ralpha I50I genotype was significantly increased in HSP group compared with HSN (58.88% vs. 44.26%; P = 0.002; OR = 1.804) and HES (58.88% vs. 42.00%; P = 0.038; OR = 1.978). The present study for the first time suggests an association of IL-4Ralpha I50 allele with increased likelihood of HIV-1 infection in North Indian population. Further studies are required to confirm these findings and understand the effect of IL-4Ralpha polymorphism on the outcome of HIV-1 infection.