Mouse double-minute 2 homologue (MDM2) is a key negative regulator of p53, a tumor suppressor gene that initiates cell cycle arrest and apoptosis in response to DNA damage and other cellular stresses. A T > G polymorphism found in the promoter region of MDM2 (SNP309) increases MDM2 expression and thereby attenuates p53 activity. We genotyped the MDM2 polymorphism SNP309 in endometrial cancer case-control studies nested within the Nurses' Health Study (454 cases and 1,132 controls) and the Women's Health Study (137 cases and 411 controls). Due to a significant difference in genotype distribution by ethnicity, we restricted our analyses to Caucasians. We calculated odds ratios and 95% confidence intervals using conditional and unconditional logistic regression adjusted for age at menarche, parity and age at first birth, postmenopausal hormone use at diagnosis, age at menopause and menopausal status at diagnosis, first-degree family history of colon cancer, body mass index at diagnosis, and cigarette smoking status at diagnosis. Women with a heterozygous genotype had no greater risk whereas those with a homozygous variant genotype had a greater risk than women with a wild-type genotype for the MDM2 SNP309 (covariate-adjusted odds ratio, 1.87; 95% confidence interval, 1.29-2.73) for endometrial cancer. We observed no association between age at diagnosis and genotype. Women carrying two copies of the MDM2 SNP309 variant may be at greater risk of endometrial cancer.