We evaluated whether genetic variability, as well as menopausal status, modify the association between coffee intake and risk of ovarian cancer. Risk factor information and biologic specimens from three large epidemiological studies, the Nurses' Health Study (NHS), NHSII, and the New England based Case-Control Study of ovarian cancer (NECC) were pooled resulting in 1,354 ovarian cancer cases and 1,851 controls for analysis. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using conditional (NHS/NHSII) and unconditional (NECC) logistic regression. Coffee consumption was not associated with overall risk (OR = 0.99; 95% CI 0.77-1.28); however, there was a suggested increased risk of ovarian cancer among premenopausal women in the NECC only and an inverse association among postmenopausal women. Carrying one or both of the variant CYP19013 A or CYP19027 G alleles was associated with an 18% increased (P for trend = 0.02) and 15% decreased (P for trend = 0.05) risk of ovarian cancer, respectively. Variation in CYP1A1, CYP1A2, or CYP2A6 did not explain the inconsistent reports of coffee intake and risk. Furthermore, we did not observe any clear gene-environment interactions between caffeine metabolizing genes and ovarian cancer. Future studies evaluating mechanisms by which coffee mediates this relationship are warranted.