BACKGROUND: Breast density classification is largely determined by mammography, making the timing of the first screening mammogram clinically important. OBJECTIVE: To evaluate the cost-effectiveness of breast cancer screening strategies that are stratified by breast density. DESIGN: Microsimulation model to generate the natural history of breast cancer for women with and those without dense breasts and assessment of the cost-effectiveness of strategies tailored to breast density and nontailored strategies. DATA SOURCES: Model parameters from the literature; statistical modeling; and analysis of Surveillance, Epidemiology, and End Results-Medicare data. TARGET POPULATION: Women aged 40 years or older. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTION: No screening; biennial or triennial mammography from age 50 to 75 years; annual mammography from age 50 to 75 years for women with dense breasts at age 50 years and biennial or triennial mammography from age 50 to 75 years for those without dense breasts at age 50 years; and annual mammography at age 40 to 75 years for women with dense breasts at age 40 years and biennial or triennial mammography at age 50 to 75 years for those without dense breasts at age 40 years. OUTCOME MEASURES: Lifetime costs and quality-adjusted life-years (QALYs), discounted at 3% annually. RESULTS OF BASE-CASE ANALYSIS: Baseline screening at age 40 years followed by annual screening at age 40 to 75 years for women with dense breasts and biennial screening at age 50 to 75 years for women without dense breasts was effective and cost-effective, yielding an incremental cost-effectiveness ratio of $36 200 per QALY versus the biennial strategy at age 50 to 75 years. RESULTS OF SENSITIVITY ANALYSIS: At a societal willingness-to-pay threshold of $100 000 per QALY, the probability that the density-stratified strategy at age 40 years was optimal was 56% compared with 6 other strategies. LIMITATION: Findings may not be generalizable outside the United States. CONCLUSION: The study findings advocate for breast density-stratified screening with baseline mammography at age 40 years. PRIMARY FUNDING SOURCE: National Cancer Institute.