Aromatase, encoded by the CYP19A1 gene, is a key enzyme in estradiol biosynthesis, which catalyzes the conversion of androstenedione and testosterone to estrone and estradiol, respectively. Given the critical role of estrogen in the development of endometrial cancer risk, we evaluated genetic polymorphisms of the CYP19A1 gene, including rs1065779, rs700519, rs28566535, rs752760, and rs1870050, in association with endometrial cancer in a population-based case-control study conducted in Shanghai, China. Genotypes of 1,040 incident endometrial cancer cases and 1,031 frequency-matched controls were included in the study. We applied a logistic regression model to derive adjusted odds ratios (OR) and their 95% confidence intervals (95% CI). Six common haplotypes with a frequency >or=5% were estimated; the highest frequency haplotype was GCACA (27.8% in cases and 26.2% in controls). We observed an inverse association between CYP19A1 haplotype TCATC and endometrial cancer in our population (OR, 0.76; 95% CI, 0.62-0.92). An inverse association was found between endometrial cancer and single nucleotide polymorphism rs1870050 in the promoter region with ORs of 0.81 (95% CI, 0.68-0.97) and 0.58 (95% CI, 0.42-0.80) for the AC and CC genotypes, respectively. We observed a multiplicative interaction between single nucleotide polymorphism rs700519 and body mass index among postmenopausal women (P = 0.01), with stronger associations between rs700519 genotypes and endometrial cancer risk among heavier (body mass index, >or=25) postmenopausal women. In summary, our data show that polymorphisms in the CYP19A1 gene may contribute to endometrial carcinogenesis.