OBJECTIVES: To estimate the cost-effectiveness of denosumab vs. the most commonly used therapy (alendronate+colecalciferol) in treatment of post-menopausal osteoporosis (PMO) in Portugal. METHODS: A Markov cost-utility life-cycle model with six month cycle length was used. The analysis was undertaken from a National Health Service (NHS) perspective. Efficacy data for denosumab was taken from the FREEDOM randomized double-blind clinical trial and for the comparator from a meta-analysis conducted by NICE. Epidemiological data were derived from Portuguese sources and complemented with Swedish data whenever the former were unavailable. Resource use data were collected through a modified Delphi panel of Portuguese experts (including rheumatologists, GPs and orthopedic surgeons). Resources were valued using various national sources on unit costs. EQ-5D decrements per fracture were based on the international literature. Expected persistence differences between treatments were also considered. Deterministic sensitivity analysis was conducted on key variables (including costs, utilities, impact of fractures on mortality, non-inclusion of sub-optimal persistence, comparator’s price, age and T-score for treatment initiation). Probabilistic sensitivity analysis was performed on the model’s treatment effects, fracture costs, EQ-5D fracture decrements and persistence rate differences. RESULTS: Considering an annual NHS cost of €382.20 for denosumab, the estimated ICER was €14,487 per QALY gained. The model predicts that, relative to the comparator, denosumab would prevent 12 hip, 22 vertebral, 2 wrist and 1 other osteoporotic fractures, per 1000 patients, over a 10 year period. Deterministic sensitivity analysis identified the absence of a persistence effect and the use of generic alendronate price as the most sensitive parameters (22,906, 20,817 €/QALY, respectively).  The probability of cost-effectiveness ranged between 91% and 64% (willingness to pay set at 50,000 and 20,000 €/QALY, respectively). CONCLUSIONS: Results from the model suggest that, compared to the most commonly used strategy (alendronate+colecalciferol), denosumab is a cost-effective therapy in the treatment of PMO in Portugal.