INTRODUCTION: Metastatic melanoma (MM) is the deadliest form of skin cancer.  It’s associated with high mortality with a median overall survival (OS) of 6 to 9 months. Ipilimumab is the first agent to improve the survival of metastatic melanoma patients and to provide long-term benefit to a proportion of patients treated within phase II/III studies and expanded access programs. OBJECTIVES: To evaluate the cost-effectiveness of ipilimumab in previously treated patients for advanced melanoma compared to Best Supportive Care (BSC) from a Portuguese national payer perspective. METHODS: A three-state Markov model with stable disease, progression and death was developed. The model assumed three-week cycles, and the analysis assumed a lifetime time horizon. Costs and consequences were discounted at 5%. Patient-level data from the pivotal Phase III MDX010-20 trial was used to describe the survival of ipilimumab 3mg/kg and BSC (based on the gp100 arm of the trial). Extrapolation methods were used to model long-term survival beyond the trial. Clinical practice and resource utilization were assessed from a survey of Portuguese oncologists and dermatologists.  Unit costs were obtained from official sources and outcomes were described in life years (LY) gained.  One-way and probabilistic SA were also undertaken. RESULTS: Ipilimumab was associated with an additional gain of 1.29 LY when compared to BSC, with an incremental cost-effectiveness ratio of €53,579/LY. Results were most sensitive to different survival extrapolation assumptions and the treatment cost.  Probabilistic SA showed a >95% likelihood that ipilimumab is cost-effective at a willingness to pay threshold of €59,000/LY. CONCLUSIONS: Ipilimumab offers a significant survival benefit when compared with BSC, but at a higher cost. Given the high unmet need, small number of advanced melanoma patients and robust sensitivity analyses; it is likely that ipilimumab represents a cost-effective treatment for previously treated advanced melanoma patients in Portugal.