AbstractEndogenous estrogen exposure is an important determinant of endometrial cancer risk. Aromatase, encoded by CYP19, catalyzes the aromatization of androstenedione and testosterone to estrone and estradiol, respectively. Several common genetic polymorphisms in CYP19 have been identified, including a TCT insertion/deletion and a (TTTA)n repeat polymorphism in intron IV as well as a 3′UTR C/T polymorphism. We evaluated these 3 polymorphisms plus an additional 9 noncoding polymorphisms as individual genotypes and predicted haplotypes as risk factors for endometrial cancer using a nested case‐control study design. Invasive endometrial cancer cases (n = 222) and matched controls (n = 666) were identified among participants in the Nurses' Health Study who had provided a blood sample in 1989–1990 (n = 32,826). We estimated haplotypes from unphased genotype data spanning >123 kb of CYP19. Six haplotypes constructed from 10 SNPs were estimated with a frequency ≥5%. The highest prevalence haplotype (33% among cases, 28% among controls) was significantly associated with endometrial cancer risk (p = 0.03). Loci with variant alleles that comprise the risk haplotype were independently associated with endometrial cancer, with relative risk estimates ranging from 1.68 (95% CI 1.13–2.48) to 2.07 (95% CI 1.33–3.23), comparing variant allele carriers to wild‐type homozygotes. We observed significant interactions between menopausal status and 2 of the high‐risk loci (p = 0.03 and p < 0.01), with >2‐fold increased risk for variant allele carriers who were postmenopausal but no association between genotype and endometrial cancer among premenopausal women. We evaluated associations between CYP19 haplotypes and plasma steroid hormone levels. The haplotype associated with endometrial cancer risk is also significantly associated with the ratios of estrone to androstenedione and estradiol to testosterone, the products and substrates of the enzyme aromatase, encoded by CYP19. Our data suggest that there is a high‐frequency CYP19 haplotype related to higher estrogen to androgen ratios and increased risk of endometrial cancer and that this association may primarily pertain to postmenopausal women. (Supplementary material for this article can be found on the International Journal of Cancer website at http:www.interscience.wiley.com/jpages/0020‐7136/suppmat/index.html.) © 2005 Wiley‐Liss, Inc.