OBJECTIVES This analysis assessed the cost effectiveness of ipilimumab 3mg/kg as first-line treatment for metastatic melanoma. As ipilimumab has an existing second-line recommendation, the decision problem is ipilimumab first-line followed by best supportive care (BSC), compared with Scottish clinical practice - dacarbazine or vemurafenib first-line followed by ipilimumab. METHODS In line with SMC requirements, an area under the curve model was built comparing first-line ipilimumab, dacarbazine and vemurafenib. The model utilised progression, survival and utility data from CA184-024 for ipilimumab/dacarbazine and dacarbazine, survival data from MDX010-20 for ipilimumab second-line, and survival and progression data from BRIM-3 for vemurafenib. MDX010-20 and observational data, using the approved regimen, were tested within scenario analyses assessing the performance of ipilimumab 3mg/kg at first-line. 2013 costs were taken from Scottish or UK official sources. RESULTS Economic analysis, including patient access schemes for ipilimumab and vemurafenib, shows that ipilimumab first-line followed by BSC is cost-effective versus dacarbazine first-line followed by ipilimumab (incremental costs: £10,502, incremental quality-adjusted life-years [QALYs]: 0.33, incremental cost-effectiveness ratio [ICER]: £31,481). Compared with ipilimumab first-line followed by BSC, the sequence vemurafenib first-line followed by ipilimumab is associated with incremental QALYs (0.26) but also incremental costs (£33,306), resulting in a not cost-effective cost/QALY trade-off (ICER = £126,482), i.e. ipilimumab first-line should be the preferred option. A scenario analysis that compared ipilimumab first-line with vemurafenib first-line alone resulted in ipilimumab being the dominant treatment option. Comprehensive sensitivity analyses identified survival parameters as having the largest impact on model results. Ipilimumab remained cost-effective at a threshold of £50,000 per QALY gained against both comparators. CONCLUSIONS First-line ipilimumab treatment for melanoma is cost-effective, and as a first-line option it would expand clinician choice, enabling selection of the most appropriate therapy for patients depending on their disease characteristics and BRAF mutation status.