AbstractHuman leukocyte antigen (HLA)‐G molecule acts as a potential factor for the regulation of immune responses and its expression in virus‐infected cells may enable them to escape immunosurveillance. Besides its polymorphic promoter region, the 3′ untranslated region (UTR) seems to play an important role in regulating HLA‐G expression. In this study, we investigated the influence of HLA‐G 14 bp (rs66554220) and +3142 (rs1063320) polymorphisms in 179 women with active human papillomavirus (HPV) infection and 143 age‐matched, unrelated, HPV‐negative, normal Chinese Han population. Our findings showed that frequency of the allele +3142 C [31.3% vs 44.4%, odds ratio (OR) = 0.57, Pc < 0.01] and the genotype +3142 CC (10.6% vs 21.7%, OR = 0.43, Pc = 0.012) was significantly decreased in HPV infected patients compared with normal controls. Furthermore, the haplotype −14 bp/C was associated with a reduced risk for HPV infection (OR = 0.57, Pc = 0.001). Our findings also showed that HLA‐G homozygous +14 bp/+14 bp genotype was significantly associated with an increased risk for HPV18 infection (OR = 12.95, P < 0.01), whereas HLA‐G heterozygous +14 bp/−14 bp genotype increased risk for HPV58 (OR = 5.55, P < 0.05). Furthermore, frequency of the haplotype +14 bp/G was significantly increased in HPV18 infected patients (60.0% vs 27.3%, OR = 4.00, Pc < 0.05). Taken together, our results supported a role of the HLA‐G 3′ UTR polymorphisms as a susceptible factor for the active HPV infection, and suggested a possible interference of the HLA‐G molecule in the response to virus infection.