Background: Patients (pts) diagnosed with unresectable stage III or IV melanoma have 5-year survival rates of 15-20%. Recent FDA approved treatment options include pembrolizumab (PEM), nivolumab (NIVO), and ipilimumab (IPI), and these are associated with improved survival, particularly for pts with BRAF wild-type tumors. To inform policy makers regarding the value of treatments, we compared the cost-effectiveness of immunotherapy strategies. Methods: We developed Markov models, utilizing a US Medicare perspective and lifetime horizon, to estimate costs (2015 US$) and quality-adjusted life years (QALYs) for various combinations and sequences of PEM, NIVO, IPI, and chemotherapy. Each sequence was compared to the baseline sequence with dacarbazine (chemo) as a 1^st line treatment strategy followed by immunotherapy. Health states were defined for each treatment line and transition probabilities between health states were derived from progression-free and overall survival data. Survival data, frequency of adverse effects, and rates of discontinuation were obtained from randomized phase III trials. We evaluated model uncertainty through univariate and probabilistic sensitivity analyses. Results: The table reports incremental costs, effectiveness, and incremental cost-effectiveness ratio (ICER) of immunotherapy-based strategies compared with dacarbazine followed by immunotherapy. Results were most sensitive to changes in drug acquisition costs and rates of discontinuation for immunotherapeutic agents. Conclusions: Our results find that single agent NIVO or PEM followed by IPI are the most cost-effective immunotherapy-based treatment strategies in pts with newly diagnosed BRAF wild-type unrespectable stage III or IV melanoma. When the cost of IPI is decreased by 50%, the cost of NIVO must be lowered to ≤ $765 for the treatment strategy of 1st line NIVO + IPI to fall below the willingness-to-pay threshold of $150,000.