Background: Comparative data on cancer therapy health care resource utilization (HCRU) and associated cost will be helpful as value-based healthcare moves forward. BRAF & MEK inhibitor combinations are considered first-line treatment for BRAF (V-600) metastatic melanoma (MM), although head-to-head trials are lacking. We aimed to establish the real-world HCRU and 6-month (mo) cost-of-care in V-600 MM treated with BRAF & MEK inhibitor therapy. Methods: A single data team in 2018 performed a multicenter, retrospective chart audit of adult patients with BRAF V-600 MM. Four institutions from across the US with patients who had received either dabrafenib + Trametinib (DT) or vemurafenib + cobimetinib (VC) were enrolled. In the most recent 12 mo period, data was captured from the start of therapy for 6 mo or until therapy was stopped. Dose change or stoppage was accessed for cause (toxicity, disease, death, other). Variables included hospitalization, emergency room (ER), all clinic visits (routine + extra), scans, labs, and treatment drug (AWP). Medicare reimbursed rates were applied for cost estimates. Utilization and costs were measured on per patient per month (PPPM) bases and the total cost over 6 mo for each combination. Results: Of the 42 patients included, 34 and 8 were initiated on DT and VC, respectively. Proportions of patients with extra clinic visits and hospital admissions were 79%, 15% and 75%, 13%, respectively for DT and VC. PPPM hospitalization was the lowest among the resources utilized 0.24 for DT and 0.17 for VC. A higher proportion of VC patients (75%) had a dose reduction due to drug toxicity compared with 29% of patients treated with DT (P < 0.05). Discontinuation rates were the same between both combinations (0.26). 32 patients had completed 6 mo of treatment (26 DT and 6 VC). For those DT, the mean total costs including drug and the mean monthly total costs were $157,253 and $26,209 compared to $107,240 and $17,873 for VC, respectively. The mean total costs for hospitalization were $10,562 for DT and $7,456 for VC. The mean total costs for the drug were $145,012 for DT and $97,924 for VC. Conclusions: The 6-month total cost-of-care for the treatment of first-line V-600 MM with DT was $157,253 and $107,240 for VC, mostly attributable to drug cost. In a value-based healthcare system, total 6-month cost-of-care may help distinguish between equally effective regimens.