OBJECTIVES: To assess the cost-effectiveness of denosumab and zoledronate in preventing fractures related to osteoporosis in postmenopausal women from the private healthcare sector perspective in Brazil. METHODS: A previously validated Markov model comprising eight health states (no fracture, hip, vertebral, wrist and other osteoporotic fractures, post hip and post vertebral fractures, and death) quantified lifetime costs and benefits within six-month intervals. Analyzed population consisted of postmenopausal women ≥72 years. Age-related risk fracture was modeled and fracture-specific risk reductions of each targeted therapy were computed. Efficacy data were derived from published randomized clinical trials. The analysis included direct costs using ex-factory drug prices. Medical and laboratory costs came from the Brazilian Medical Association reimbursement list. Fracture-related (i.e., hospitalization, surgery) and follow-up (i.e., rehabilitation) costs were extracted from a private healthcare database (BI2im). Costs were reported in 2012 Brazilian currency (1BRL=0.52USD). Outcomes assessed were 10-year fracture event incidence and quality-adjusted life years (QALYs). Costs and benefits were discounted 5% yearly. Univariate and multivariate (probabilistic) sensitivity analyses tested model robustness. RESULTS: Average morbidity costs were BRL2,722 and BRL2,839 for denosumab and zoledronate, respectively. Intervention costs were BRL5,153 for denosumab and BRL5,481 for zoledronate. Lifetime cost difference between alternatives was BRL446 per patient treated. Ten-year fracture incidence was lower with denosumab: reductions of 0.5% and 1.5% for hip and vertebral fractures, respectively, over zoledronate. Average QALYs were 6.861 and 6.841 for denosumab and zoledronate. Denosumab reduced fracture incidence and improved QALYs at a lower cost. Denosumab remained cost-efffective after changes in individual model parameters (up to 20% variability), considering a willingness-to-pay of BRL57,000/QALY gained (3x Brazilian GDP/capita). Multivariate sensitivity analysis, showed 89.2% of iterations favored denosumab. CONCLUSIONS: Denosumab was cost-effective over zoledronate from the private healthcare setting perspective in Brazil, adding gains in benefits at a lower cost in preventing osteoporotic fractures in postmenopausal women.