A functional T to G germline polymorphism in the promoter region of murine double-minute 2 homolog single nucleotide polymorphism 309 (MDM2-SNP309) has been reported to profoundly accelerate tumor formation, suggesting that it may also represent a powerful cancer predisposing allele. In this study, MDM2-SNP309 was examined in a total of 400 blood samples from 108 normal, 88 cervical, 119 endometrial and 85 ovarian cancer cases using two independent polymerase chain reaction assays for each allele. When the MDM2-SNP309 genotype was classified into two subgroups of TT+TG and GG, the GG genotype was associated with an increased risk for the development of endometrial cancer (odds ratio [OR] = 1.91, 95% confidence interval [CI] = 1.05 to 3.47) compared with the TT+TG genotype (P = 0.0353). The G allele also increased the risk of endometrial cancer (OR = 1.20, 95% CI = 0.83 to 1.74) compared with the T allele, but no statistical difference was found (P = 0.3333). The homozygous GG genotype was also associated with postmenopausal status and type I endometrial cancer (P = 0.0306 and 0.0326, respectively). There was no significant difference in the genotype or allele prevalence between control subjects and cervical or ovarian cancer patients. These results suggest that homozygous GG genotype of MDM2-SNP309 may be a risk factor for postmenopausal and type I endometrial cancer in a Japanese population.