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Importance Multiple effective first-line systemic treatment options are available for patients with advancedBRAF-mutated melanoma. A lack of head-to-head randomized clinical trials (RCTs) comparing targeted and immunotherapies leaves uncertainty regarding optimal first-line treatment. Objective To estimate the relative efficacy and safety of systemic therapies for advanced, treatment-naive,BRAF-mutated melanoma. Data Sources We searched MEDLINE, Embase, and the Cochrane Central Registry of Controlled Trials for phase 2 or 3 RCTs published up until April 29, 2016. Study Selection We included RCTs in which at least 1 intervention was a targeted (BRAForMEK) or an immune checkpoint (cytotoxic T-lymphocyte–associated antigen 4 [CTLA-4] or programmed cell death 1 [PD-1]) inhibitor. Data Extraction and Synthesis Two reviewers performed study selection, data abstraction, and risk of bias assessment. We performed a Bayesian network meta-analysis using a fixed-effect model to combine direct comparisons with indirect evidence. We estimated hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and odds ratios (OR) for objective response rate (ORR) and serious adverse events. Results Sixteen eligible articles reporting 15 RCTs involving 6662 patients assigned to 1 of 10 treatment strategies were included. BothBRAF/MEKand PD-1 were associated with improved OS benefit compared with all other treatments except CTLA-4/granulocyte macrophage colony-stimulating factor. There was no significant difference in OS betweenBRAF/MEKand PD-1 (HR, 1.02; 95% credible interval [CrI], 0.72-1.45). The network meta-analysis showed a significant advantage ofBRAF/MEKcompared with all other treatment strategies for PFS.BRAF/MEKwas associated with higher ORR (OR, 2.00; 95% CrI, 1.64-2.45) compared withBRAFalone, with both being superior in achieving ORR compared with other treatments. Chemotherapy and PD-1 were associated with lowest risk of serious adverse events. There was no significant difference in the risk of serious adverse events between chemotherapy and PD-1 (OR, 1.00; 95% CrI, 0.74-1.34). Conclusions and Relevance Compared with other treatments,BRAF/MEKand PD-1 inhibition significantly improved OS. The favorable safety profile of PD-1 inhibitors supports using this option as first-line therapy in circumstances where rapid response is not a priority.