Background: To evaluate the incremental short- and long-term benefits and harms of primary prevention with risk reducing medication in high-risk women receiving screening mammography. Methods: We adapted an established, validated Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer discrete event microsimulation model developed to synthesize data the impact of using risk-reducing medication and annual mammography among women with a 3% or higher five-year risk of developing breast cancer. We also examined the effects of supplemental MRI. The model follows a simulated cohort of millions of US women from birth to death. We used large observational and clinical trial data to derive input parameters for cohort-specific birth rates, breast cancer risk, incidence and stage, screening performance, survival by age, stage, and subtype, treatment efficacy, and other cause mortality. Breast cancer risk was modeled based on family history, breast density, age and history of past breast biopsy. We compared two strategies, annual 3D mammography alone vs. annual 3D mammography and a 5-year course of risk reducing medication at various starting ages, and adding MRI to each approach. Outcomes included the benefits of risk-reducing drugs (avoiding breast cancer) and screening (stage, breast cancer death). Harms included drug side effects and screening false positives and overdiagnosis. Sensitivity analysis tested the impact of uncertainty in model inputs and assumptions on results. Results: Compared to mammography alone, adding risk reducing medication could decrease invasive breast cancer incidence by 30%, and breast cancer deaths by 30% (Table). However, due to reduction in breast cancer incidence, risk reducing medication could result in a 3% increase in false positive results; adding MRI increases benefits but also increases false-positive results. Benefits and harms of risk reducing medication and breast cancer screening strategies for women at high-risk of developing breast cancer. Conclusions: Risk-reducing mediation reduces the risk of hormone-receptor positive breast cancer, and combining this with mammography (and/or MRI) improves earlier detection. Additional work is ongoing to incorporate adverse effects of therapy. Simulation modeling can be used to provide individualized data to facilitate discussions about breast cancer prevention and early detection among high-risk women seen in clinical practice.