OBJECTIVES: Raloxifene (RLX) reduces the risk of vertebral fractures and invasive breast cancer (IBC). The National Osteoporosis Foundation (NOF) has recommended a threshold for treatment initiation of 10-year major fracture risk of 20%, but given RLX’s beneficial efficacy on IBC it may be clinically beneficial and cost-effective to treat women with RLX even if they do not meet this threshold. The aim was to identify how 5-year IBC risk affects the cost-effectiveness of treating younger postmenopausal women who do not meet the 20% absolute fracture risk threshold with RLX compared to no intervention. METHODS: A micro-simulation model populated with data specific to American women was used to quantify the costs and benefits of 5-year treatment with RLX from a societal perspective. Possible events were vertebral fracture, IBC, VTE and death. EQ-5D societal health state values were used to estimate quality-adjusted life years (QALYs). The population was selected based on 10-year major fracture risk as estimated with FRAX® (5-19.9%) and 5-year IBC risk as estimated with Gail risk model (1-5%). RESULTS: The cost per QALY gained ranged from US$17,100 to 93,000. RLX was progressively cost-effective with increasing fracture risk and IBC risk holding age constant. At lower fracture risk in combination with lower IBC risk or when no preventive RLX effect on IBC was assumed, the cost-effectiveness of RLX decreased markedly and was not cost-effective given a willingness-to-pay of US$50,000. At fracture risk of 15-19.9% RLX was cost-effective also in women at lower IBC risk. CONCLUSIONS: RLX is potentially cost-effective in young postmenopausal women at elevated IBC risk who do not meet the suggested NOF 10-year fracture threshold. This highlights the importance of considering a woman’s full risk profile when deciding which anti-osteoporosis treatment to recommend.