Prior studies have suggested that vitamin D may reduce ovarian cancer risk. Thus, we examined whether three single nucleotide polymorphisms (SNP) in the vitamin D receptor (VDR) gene (Fok1, Bsm1, Cdx2) were associated with risk of epithelial ovarian cancer in a retrospective case-control study (New England Case-Control study, NECC) and a nested case-control study of three prospective cohort studies: the Nurses' Health Study (NHS), NHSII, and the Women's Health Study. Data from the cohort studies were combined and analyzed using conditional logistic regression and pooled with the results from the NECC, which were analyzed using unconditional logistic regression, using a random effects model. We obtained genotype data for 1,473 cases and 2,006 controls. We observed a significant positive association between the number of Fok1 f alleles and ovarian cancer risk in the pooled analysis (P(trend) = 0.03). The odds ratio (OR) for the ff versus FF genotype was 1.26 [95% confidence interval (CI) = 1.01-1.57]. Neither the Bsm1 (P(trend) = 0.96) or Cdx2 (P(trend) = 0.13) SNPs were significantly associated with ovarian cancer risk. Among the prospective studies, the risk of ovarian cancer by plasma vitamin D levels did not clearly vary by any of the genotypes. For example, among women with the Fok1 FF genotype, the OR comparing plasma 25-hydroxyvitamin D >or=32 ng/mL versus <32 ng/mL was 0.66 (95% CI, 0.34-1.28), and among women with the Ff or ff genotype the OR was 0.71 (95% CI, 0.43-1.18). Our results of an association with the Fok1 VDR polymorphism further support a role of the vitamin D pathway in ovarian carcinogenesis.