ObjectivesWhile emerging evidence supports a possible link between depression and ovarian cancer progression, no prospective studies have explored the association with ovarian cancer risk. MethodsWe prospectively followed 77,451 women from the Nurses' Health Study (1992–2010) and 106,452 women from the Nurses' Health Study II (1993–2011). Depression was defined as having one or more of the following: a 5-item Mental Health Index (MHI-5) score≤52, antidepressant use, or physician-diagnosed depression. Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between depression and incident ovarian cancer. ResultsWe documented 698 incident cases of epithelial ovarian cancer during follow-up. In multivariable analyses, depression assessed 2–4years before cancer diagnosis was associated with a modestly higher incidence of ovarian cancer (HR=1.30, 95% CI 1.05–1.60). Compared to women with persistent negative depression status, the adjusted HRs were 1.34 (95% CI 1.01–1.76) for women with persistent positive depression status and 1.28 (95% CI 0.88–1.85) for women with worsening depression status over follow-up. The association did not appear to vary by ovarian cancer risk factors or tumor characteristics. ConclusionsOur findings suggest that depression may be associated with a modestly increased risk of ovarian cancer. Given the relatively high prevalence of depression in women, future work in larger prospective human studies is needed to confirm our results.