Estrogen exposures play a critical role in the development of endometrial cancer. Genetic variation in the estrogen metabolism UGT1A1 gene may modify the effect of estrogenic exposures on endometrial cancer risk. We tested this hypothesis in a population-based case-control study of 1,047 endometrial cancer cases and 1,035 controls who completed an in-person interview and were genotyped for the UGT1A1 polymorphisms rs2070959 (A/G), rs887829 (G/A), and rs8175347 (6/7 TA repeats). Estrogen exposure-related factors evaluated include menstrual characteristics, oral contraceptive use, body mass index, waist-hip ratio, and soy food intake. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. The homozygote variant genotype (G/G) of the rs2070959 polymorphism was significantly associated with a reduced risk of endometrial cancer (odds ratio, 0.5; 95% confidence interval, 0.3-0.8). No significant associations between endometrial cancer risk and genotype were seen for the rs887829 and rs8175347 polymorphisms. Analysis of the joint effects of genotype and markers of estrogen exposure found the lowest risk of endometrial cancer among those with the homozygous variant genotype of the rs2070959 polymorphism and who were postmenopausal, had low body mass index, and had low soy food intake, although a test for multiplicative interaction was not significant. Taken together, these data suggest that the G/G genotype (rs2070959) in the UGT1A1 gene may decrease the risk of endometrial cancer and that this effect is most evident among women with low levels of endogenous estrogen exposure or with low soy food intake.