OBJECTIVES: To assess the cost-effectiveness of breast cancer risk assessment in primary care, with chemoprevention with tamoxifen offered to high-risk women. METHODS: A Markov model was developed to simulate the incidence, health consequences, and costs of invasive breast cancer (IBC) and other clinical events associated with a 5-year course of tamoxifen. Cohorts at ages 50, 55, and 60 were stratified by 5-year cancer risk based on the Gail model. Treatment criteria were defined according to alternative risk thresholds of 1.67% to 6%. Acceptance of (70%) and compliance with (68%) chemoprevention were assumed to be imperfect. Women receiving tamoxifen were assumed to be at decreased risk for IBC and vertebral fracture, and increased risk for endometrial cancer, stroke, and venous thromboembolic events. Breast cancer incidence and survival were derived from SEER. Other model parameters, including costs and utilities, were estimated from published literature and clinical trial data. We discounted costs (2006 US dollars) and quality-adjusted life years (QALYs) at 3%/year. RESULTS: : For 50-year-old women, risk assessment and chemoprevention based on a 5-year cancer risk of 4% or greater results in an incremental cost-effectiveness ratio (ICER) of $49,900 compared to no risk assessment. Expanding the criterion for chemoprevention to 3%, 2%, and 1.67% leads to incremental cost-effectiveness ratios of $54,400, $106,000, and $163,000 per QALY, respectively. Thresholds higher than 4% were weakly dominated. At age 60, ICERs ranged from $35,300 to $1.3 million per QALY as the treatment threshold was lowered from 6% to 1.67%. At age 65, thresholds below 5% were dominated. CONCLUSION: Risk assessment and chemoprevention is cost-effective at a $100K/QALY threshold at ages 50-65, but more selective criteria for chemoprevention at older ages is required to achieve any given cost-effective criterion.