Although the role of estrogen in the etiology of ovarian cancer is uncertain, there is increasing evidence that hormone replacement therapy is a risk factor for ovarian malignancy. The production of estrogen involves the conversion of androgens via P450 aromatase, encoded by the CYP19A1 gene. Genetic variation in two CYP19A1 single-nucleotide polymorphisms (SNPs), rs749292 and rs727479, has been found to produce 10-20% increases in estrogen levels among postmenopausal women. We tested the hypothesis that these SNPs were associated with the risk of ovarian cancer in a population-based case-control study in Hawaii, including 367 histologically confirmed epithelial ovarian cancer cases and 602 age- and ethnicity-matched controls. The A allele of rs749292 was positively associated with ovarian cancer risk in a codominant model for all races combined (AG versus AA genotype: odds ratio (OR), 1.48 and 95% confidence interval (CI, 1.07-2.04); GG versus AA: OR, 1.87 (CI, 1.24-2.82); P(trend)=0.002). Similar significant associations of the rs749292 A allele on the risk of ovarian cancer were found among Caucasian and Japanese women. No relation of the rs727479 SNP to ovarian cancer risk was observed overall, although Caucasian women carrying the variant A allele compared with women with an CC genotype had an OR of 2.91 (CI, 1.15-7.37). These data suggest CYP19A1 variants may influence susceptibility to ovarian cancer.