Human leukocyte antigen-G (HLA-G) expression is a potential factor for the pathogenesis of virus infection. A 14 bp insertion/deletion polymorphism (rs16375) in the 3'-untranslated region of the HLA-G gene is involved in the stability of HLA-G mRNA and HLA-G protein expression. Therefore, the HLA-G 14 bp polymorphism might be involved in human cytomegalovirus (hCMV) infection. To test a possible association between the HLA-G 14 bp deletion/insertion polymorphism and the active hCMV infection, in this study, a total of 54 patients with active hCMV infection and 165 age- and sex-matched, unrelated, normal Chinese Han population were genotyped for the 14 bp insertion/deletion polymorphism. Association of 14 bp polymorphism with hCMV urine DNA copies and the odds ratio (OR) of the polymorphism as a risk factor for active hCMV infection were analyzed. Our results showed that the prevalence of -14 bp/ -14 bp genotype in active hCMV patients was markedly increased [P(c) = 0.00034, OR = 3.31, 95% confidence interval (CI): 1.77-6.18], and similar significance was also observed for the frequency of -14 bp allele (P c = 0.0023, OR = 2.24, 95% CI: 1.38-3.64) when compared with that of healthy controls. Furthermore, urine hCMV DNA copies in patients with the -14 bp/ -14 bp genotype were significantly higher than those in patients with the +14 bp/ +14 bp genotype (P = 0.041). Our findings support a potential role of HLA-G 14 bp insertion/deletion polymorphism as a susceptible factor for the active hCMV infection.