Federal legislation proposes requiring that screening mammography reports to practitioners and women incorporate breast density information and that women with dense breasts discuss supplemental imaging with their practitioner given their increased risk of interval breast cancer. Instead of discussing supplemental imaging with all women with dense breasts, it may be more efficient to identify women at high risk of advanced breast cancer who may benefit most from supplemental imaging.To identify women at high risk of advanced breast cancer to target woman-practitioner discussions about the need for supplemental imaging.This prospective cohort study assessed 638 856 women aged 40 to 74 years who had 1 693 163 screening digital mammograms taken at Breast Cancer Surveillance Consortium (BCSC) imaging facilities from January 3, 2005, to December 31, 2014. Data analysis was performed from October 10, 2018, to March 20, 2019.Breast Imaging Reporting and Data System (BI-RADS) breast density and BCSC 5-year breast cancer risk.Advanced breast cancer (stage IIB or higher) within 12 months of screening mammography; high advanced cancer rates (≥0.61 cases per 1000 mammograms) defined as the top 25th percentile of advanced cancer rates, and discussions per potential advanced cancer prevented.A total of 638 856 women (mean [SD] age, 56.5 [8.9] years) were included in the study. Women with dense breasts (heterogeneously or extremely dense) accounted for 47.0% of screened women and 60.0% of advanced cancers. Low advanced cancer rates (<0.61 per 1000 mammograms) occurred in 34.5% of screened women with dense breasts. High advanced breast cancer rates occurred in women with heterogeneously dense breasts and a 5-year risk of 2.5% or higher (6.0% of screened women) and those with extremely dense breasts and a 5-year risk of 1.0% or higher (6.5% of screened women). Density-risk subgroups at high advanced cancer risk comprised 12.5% of screened women and 27.1% of advanced cancers. Density-risk subgroups had the fewest supplemental imaging discussions per potential advanced cancer prevented compared with a strategy based on dense breasts (1097 vs 1866 discussions). Women with heterogeneously dense breasts and a 5-year risk less than 1.67% (21.7% of screened women) had high rates of false-positive short-interval follow-up recommendation without undergoing supplemental imaging.The findings suggest that breast density notification should be combined with breast cancer risk so women at highest risk for advanced cancer are targeted for supplemental imaging discussions and women at low risk are not. BI-RADS breast density combined with BCSC 5-year risk may offer a more efficient strategy for supplemental imaging discussions than targeting all women with dense breasts.