Childbearing and use of oral contraceptives are known to lower the risk of ovarian cancer, and it has been suggested that progesterone or progestin exposures play a role in these associations. The effects of progesterone may be mediated in part through the progesterone receptor, which exists in two functionally distinct protein isoforms, hPR-A and hPR-B. It is known that individuals carrying the A allele of the progesterone receptor gene (PGR) polymorphism, +331 A/G (rs10895068), have greater production of the hPR-B receptor isoform. We therefore examined the association between PGR +331 A/G genotype and risk of ovarian cancer in a population-based study of 490 cases and 534 controls in the state of Connecticut. Adjusted for various reproductive and other factors, a statistically significant increased risk was seen for carriage of the A allele compared with GG genotype [odds ratio (OR), 1.68; 95% confidence interval (95% CI), 1.09-2.59]. When subjects were considered separately according to menopausal status, no increased risk with the A allele was seen for premenopausal women (OR, 0.96; 95% CI, 0.46-2.02) but significantly increased risk was found for postmenopausal women (OR, 2.31; 95% CI, 1.31-4.06). Similar increased risks particularly among postmenopausal women were seen for all histologic tumor types. These findings have been observed before for breast and endometrial cancer, although not for ovary, but still suggest that an hPR-B mechanism may be involved in ovarian neoplasia.