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There remains debate about whether risk-reducing salpingo-oophorectomy (RRSO), which reduces ovarian cancer risk, also reduces breast cancer risk. We examined the association between RRSO and breast cancer risk using a prospective cohort of 17 917 women unaffected with breast cancer at baseline (7.2% known carriers of BRCA1 or BRCA2 mutations). During a median follow-up of 10.7 years, 1046 women were diagnosed with incident breast cancer. Modeling RRSO as a time-varying exposure, there was no association with breast cancer risk overall (hazard ratio [HR] 1⁄4 1.04, 95% confidence interval [CI]1⁄40.87 to 1.24) or by tertiles of predicted absolute risk based on family history (HR1⁄40.68, 95% CI1⁄40.32 to 1.47, HR1⁄40.94, 95% CI1⁄40.70 to 1.26, and HR1⁄41.10, 95% CI1⁄40.88 to 1.39, for lowest, middle, and highest tertile of risk, respectively) or for BRCA1 and BRCA2 mutation carriers when examined separately. There was also no association after accounting for hormone therapy use after RRSO. These findings suggest that RRSO should not be considered efficacious for reducing breast cancer risk. Several studies have reported evidence for a strong association between risk-reducing salpingo-oophorectomy (RRSO) and reduced breast cancer risk for BRCA1 and BRCA2 mutation carriers (1–4). Heemskerk-Gerritsen et al. (5), however, argued that these risk estimates were biased because of using an inappropriate analysis; they reported no association with breast cancer risk when RRSO was considered as a time-dependent covariate. Time-dependent analyses treat women as unexposed before RRSO and exposed after RRSO. Kotsopoulos et al. (6) confirmed the findings of Heemskerk-Gerritsen et al. (5) using a longer mean follow-up time (5.6 years vs 3.2 years). Both studies had few incident breast cancer cases among women with RRSO (122 and 21 among BRCA1 and BRCA2 mutation carriers, respectively, in Kotsopoulos et al. (6), and 36 and 6 among BRCA1 and BRCA2 carriers, respectively, in Heemskerk-Gerritsen et al. (5)), which limited power. We examined the association between RRSO and breast cancer risk for women across a wide range of familial and genetic risk using the Prospective Family Study Cohort (7). With our large cohort and long follow-up time, we were also able to investigate whether timing of RRSO mattered and whether use of hormone therapy after RRSO accounted for any lack of evidence for a decreased breast cancer risk. The Prospective Family Study Cohort includes women from the Breast Cancer Family Registry (BCFR) and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) (7). All participants provided written informed consent before enrollment, and study protocols have been approved by institutional review boards at each of the respective institutions. The current analysis used data from all women aged 18 to 79 years who were unaffected with breast B R IE F C O M M U N IC A T IO N Received: April 10, 2018; Revised: August 2, 2018; Accepted: September 7, 2018 © The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 331 JNCI J Natl Cancer Inst (2019) 111(3): djy182 doi: 10.1093/jnci/djy182 First published online November 28, 2018