Abstract Objectives: Bilateral oophorectomy permanently reduces endogenous estrogen exposure and may increase cardiovascular mortality in women. This study aimed to investigate the association between bilateral oophorectomy and cardiovascular mortality and whether this association was conditional on hysterectomy or on the use of hormone therapy at the time of study entry. Methods: A prospective cohort study of 25,338 female nurses aged ≥ 45 years within the Danish Nurse Cohort. Nurses were enrolled in 1993 or 1999 and followed until death, emigration, or end of follow-up on December 31, 2018, whichever came first. Exposure was bilateral oophorectomy. Outcome was cardiovascular mortality. Associations were estimated using Poisson regression models with log person-years as the offset. Results: A total of 2,040 (8.1%) participants underwent bilateral oophorectomy. During a mean follow-up of 21.2 (SD: 5.6) years, 772 (3.0%) nurses died from cardiovascular disease. In adjusted analyses, a 31% higher rate of cardiovascular mortality was observed after bilateral oophorectomy (aMRR 1.31; 95% CI, 0.88-1.96) compared with women who retained their ovaries. No evidence of effect modification by use of hormone therapy at baseline or by hysterectomy on the association between bilateral oophorectomy and cardiovascular mortality was observed. Conclusion: Bilateral oophorectomy may be associated with cardiovascular mortality in women, but the estimate was not statistically significant. Additionally, we were unable to make firm conclusions regarding the possible modifying role of hormone therapy and hysterectomy on this potential association. Additional studies are needed to replicate this work.