Bazedoxifene is a novel selective estrogen receptor modulator (SERM) for the prevention and treatment of osteoporosis. In addition to the therapeutic value of a new agent, evaluation of the cost-effectiveness compared with relevant alternative treatment(s) is an important consideration to facilitate healthcare decision making. This study evaluated the cost-effectiveness of bazedoxifene compared with raloxifene for the treatment of postmenopausal women with osteoporosis. The cost-effectiveness of treatment for 3 years with bazedoxifene was compared with raloxifene using an updated version of a previously validated Markov microsimulation model. Analyses were conducted from a Belgian healthcare payer perspective and, the base-case population was women (aged 70 years) with bone mineral density T-score ≤ −2.5. The effects of bazedoxifene and raloxifene on fracture risk were derived from the 3-year results of a randomized, double-blind, placebo-controlled and active-controlled study, including postmenopausal women with osteoporosis. The cost-effectiveness analysis based on efficacy data from the overall clinical trial indicated that bazedoxifene and raloxifene were equally cost-effective. When the results were examined based on the subgroup analysis of women at higher risk of fractures, bazedoxifene was dominant (lower cost for higher effectiveness) compared with raloxifene in most of the simulations. Sensitivity analyses confirmed the robustness of the results, which were largely independent of starting age of treatment, fracture risk, cost, and disutility. In addition, when the cost of raloxifene was reduced by one-half or when incorporating the raloxifene effects on reducing breast cancer, bazedoxifene remained cost-effective, at a threshold of €35,000 per quality-adjusted life-years gained, in 85% and 68% of the simulations, respectively. Under the assumption of improved antifracture efficacy of bazedoxifene over raloxifene in women with high risk of fractures, this study suggests that bazedoxifene can be considered cost-effective, and even dominant, when compared with raloxifene in the treatment of postmenopausal osteoporotic women. © 2013 American Society for Bone and Mineral Research.