OBJECTIVES: Estimate the incremental cost-effectiveness ratio (ICER) of D+T versus vemurafenib and dacarbazine for BRAF^V600mutation-positive MM from the UK NHS perspective. METHODS: A partitioned-survival model with 3 states (progression-free survival [PFS], post-progression survival, and death) and a lifetime horizon was developed. Treatment benefits were measured as gains in quality-adjusted life-years (QALYs). PFS and overall survival (OS) were derived from indirect treatment comparisons (ITCs) of D+T (from the Phase II BRF113220 study) versus vemurafenib (BRIM-3) and dacarbazine (BREAK-3). Latest OS data were adjusted for confounding effects of treatment switching, permitted upon progression in all studies. Safety data were from aforementioned trials. Costs were from the literature, a physician survey, and assumptions. Costs of medications to the NHS (incorporating available patient-access schemes), post-study anticancer therapy, routine and adverse event (AE) management, treatment initiation, and death were included. Utility data for D+T were derived from BREAK-3, with adjustment for differences in response and incidence of AEs. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: ITCs showed D+T significantly improved PFS versus vemurafenib (hazard ratio [HR] 0.38; 95% CI, 0.19–0.74) and dacarbazine (0.14; 0.08–0.28) and suggested improved OS, although not statistically significant (0.42; 0.09–1.97 versus vemurafenib and 0.26; 0.05–1.27 versus dacarbazine). Treatment with D+T was associated with a gain in QALYs versus vemurafenib and dacarbazine. The ICER for D+T was £50,603/QALY versus vemurafenib and £49,804/QALY versus dacarbazine. CONCLUSIONS: Based on results of a Phase II trial and an ITC, D+T offers improved PFS and OS versus vemurafenib and dacarbazine. Further, considering NICE’s criteria for life-extending, end-of-life treatments, D+T may be cost-effective compared with vemurafenib, the NHS’s current standard of care for patients with BRAF^V600 mutation-positive MM, although conclusions must await ongoing modelling on the basis of the Phase III, COMBI-D trial.