OBJECTIVES: Recently, options for systemic therapies for the treatment of unresectable/metastatic melanoma have expanded. The objective of this study was to evaluate the expected patient-level medication costs and health plan–level budgetary impact of new systemic therapies from a US payer perspective. METHODS: An Excel-based model was developed to evaluate the costs of systemic therapies for BRAF-mutated unresectable/metastatic melanoma patients. The model estimated 1-year expected medication costs and 5-year health plan budget impact between a current scenario with existing options and a projected scenario with existing plus new options. Both first- and second-line treatments were considered. Costs evaluated included medication, administration, monitoring, and adverse events costs. Treatment rates were based on projections. Other inputs such as incidence rates, treatment regimen and prices were derived from product inserts, literature, and publicly available sources. RESULTS: Expected 1-year medication costs for single-drug therapies were between $107,000 (Dabrafenib) and $156,000 (Nivolumab). Combination therapies cost more, with Nivolumab/Ipilimumab, Dabrafenib/Trametinib, and Vemurafenib/Cobimetinib costing $258,000, $230,000 and $211,000, respectively. More than half of the medication cost of Nivolumab/Ipilimumab was incurred in the first 3 months. Comparatively, costs of Dabrafenib/Trametinib and Vemurafenib/Cobimetinib were linearly incurred. Dabrafenib/Trametinib has the lowest rate of Grade 3 and 4 adverse events rates and associated toxicity costs while Vemurafenib/Cobimetinib has the highest. From a payer’s perspective, the total budget impact was projected to be $0.02 per member per month, of which $0.01 was due to first-line and $0.01 to second-line therapies. The budget impact was predominantly increased by medication costs. CONCLUSIONS: Combination systemic therapies cost more than single-drug therapies. Nivolumab/Ipilimumab combination had the highest 1-year expected medication cost, of which more than half was incurred in the first 3 months. From a payer’s perspective, the budget for treating unresectable/metastatic melanoma is projected to increase with the availability of new systemic therapy options.