Background: Risk reducing salpingo-oophorectomy (RRSO) is an effective option to prevent ovarian cancer in high risk women, but side effects related to premature menopause remain a barrier to uptake. Based on data linking the fallopian tube epithelium as the “cells of origin” for ovarian cancer, interval salpingectomy and delayed oophorectomy has been proposed as an alternative to RRSO. Methods: A prospective, multicenter, nonrandomized trial was performed in nine US sites, comparing change in sexual function (primary objective) and other outcomes in high risk women who self-selected ISDO or RRSO. Pre-menopausal women with a documented deleterious mutation in a gene that increased their risk for ovarian cancer were eligible. Baseline, 6 and 12 month questionnaires regarding sexual function, menopausal symptoms, and other outcomes were collected. A safety stopping rule was employed to prevent against unacceptable rate of invasive cancers being detected in the ISDO arm. Findings: Three hundred and seventeen patients completed baseline questionnaires and underwent surgery (RRSO n=147; ISDO n=144). In an age-matched comparison, there was a significantly greater fraction of women who experienced a clinically relevant decrease in sexual function in the RRSO arm compared to ISDO using the total FSFI scale (38% versus 15%, Relative Risk 2.5 (95% CI:1.3-4.8, P<0.01)). Hormone replacement therapy did not impact sexual function, but improved menopausal symptoms. There were no invasive ovarian or primary peritoneal cancers that developed in the ISDO arm, and the safety stopping rule was not triggered. Interpretation: There was a higher proportion of high risk women who experienced a clinically meaningful worsening of sexual function after undergoing RRSO, even with HRT, compared to women undergoing ISDO. The timely accrual, lack of a negative safety signal, and improved functional outcomes in women choosing ISDO provide a strong foundation on which to continue to optimize patient-centered options for ovarian cancer prevention. Trial Registration: (NCT02760849) Funding: Stand Up To Cancer-Ovarian Cancer Research Alliance-National Ovarian Cancer Coalition Ovarian Cancer Dream Team Translational Research Grant Declaration of Interests: KHL, DRN, BMN, KLR, JNB, ILR, CF, SK, ARH, JC, DJB, MH, JC, KG, DP, BS, GBC, CBP, ADD, EMS have no interests D.A.L has consulting/advisory role for Tesaro/GSK, Merck, receives research funding to institution from Merck, Tesaro, Clovis Oncology, Regeneron, Agenus, Takeda, Immunogen, VBL Therapeutics, Genentech, Celsion, Ambry, Splash Pharmaceuticals. He also is a founder of Nirova BioSense, Inc. Ethics Approval Statement: The institutional review board at The University of Texas MD Anderson Cancer Center (registration number 2015-0814) (NCT02760849) and affiliated centers including the University of Washington, Memorial Sloan Kettering Cancer Center, Mayo Clinic, Dana-Farber Cancer Institute, University of Chicago, NYU, University of Pennsylvania, and Washington University in St Louis, approved the trial. All participating patients provided informed consent.