Very strong family history and extremely dense breast tissue were absent in most 40- to 49-year-old women with breast cancer detected at screening mammography. These cancers were frequently invasive (often with nodal metastases) and treatable (hormone receptor positive). Reducing the number of women to be screened in this age group by using this risk-based approach would reduce the number of screen-detected cancers by more than 75%, thereby precluding the benefit of mortality reduction. Even using a risk-based strategy with an expanded definition of high risk that included any first-degree family history, extremely dense tissue, or both, 66% of malignancies would still be missed.