OBJECTIVES:  Nivolumab in combination with ipilimumab (the Regimen) is the first immuno-oncology combination treatment to demonstrate long-term clinical benefit for advanced melanoma patients in a trial setting. We evaluated the cost effectiveness of the Regimen for the treatment of advanced melanoma patients in England. METHODS:  A Markov state-transition model was developed in Excel^®to estimate the lifetime costs and benefits of the Regimen and the relevant comparators in England, including ipilimumab and pembrolizumab. At the time of the NICE submission, only progression-free survival data were available from the head-to-head Phase III trial (CheckMate 067) comparing the Regimen with ipilimumab. Therefore, covariate-adjusted parametric curves for time to progression and pre-progression survival were fitted based on patient-level data from the pivotal head-to-head trial, and post-progression survival for the Regimen and ipilimumab was assumed to be the same using patient-level data from trials including nivolumab and long-term ipilimumab survival data. Given the lack of patient-level data, an indirect treatment comparison was performed to estimate the hazard ratios of progression-free survival of pembrolizumab versus ipilimumab. Patient utilities and resource use data were based on trial data or sourced from the literature. Patients are assumed to receive nivolumab and pembrolizumab until there is no further clinical benefit, assumed to be the first of progressive disease as per RECIST criteria, unacceptable toxicity or two years of treatment. RESULTS:  Based on the list price of nivolumab and the assumed discounted prices for other treatments in England, the Regimen is the most cost-effective treatment option, with an incremental cost-effectiveness ratio of £23,671 per quality-adjusted life year, where ipilimumab is dominated by pembrolizumab. Two-year survival with Regimen estimated in this study is similar to published survival in a Phase II trial. CONCLUSIONS:  The analyses show that the Regimen is cost-effective for the treatment of advanced melanoma patients in England.