Patients with MBM have a poor prognosis. Nivolumab plus ipilimumab (NIVO+IPI), anti–PD-1 monotherapy (anti–PD-1), and BRAF/MEK inhibitors (BRAFi/MEKi) are first-line (1L) systemic therapies for MBM, but real-world efficacy data remain limited. This US, multisite, retrospective chart review study assessed outcomes in patients diagnosed with MBM (June 2017–June 2019) and treated with 1L NIVO+IPI (n=246), anti–PD-1 (n=112), or BRAFi/MEKi (n=114). Patients treated with whole brain radiotherapy or surgical resection were excluded. Patient characteristics in the NIVO+IPI, anti–PD-1, and BRAFi/MEKi groups, respectively, were: mean age, 60/66/61 years; ECOG performance status (PS) 3/4, 7%/12%/4%; symptomatic MBM, 55%/60%/65%; and BRAF-mutant disease (in evaluable patients), 32%/23%/100%. Median follow-up since systemic treatment initiation was 15.4, 13.3, and 14.0 months, respectively. Patients treated with BRAFi/MEKi or anti–PD-1 vs NIVO+IPI were more likely to have more extensive and larger MBM, poorer ECOG PS, and more comorbidities at baseline. In the NIVO+IPI group, median progression-free survival (PFS) was 22.6 months and median overall survival (OS) was 35.8 months. In the anti–PD-1 group, median PFS was 16.7 months and median OS was 18.7 months. In the BRAFi/MEKi group, median PFS was 15.3 months, and median OS was not reached. In the BRAF–wild-type subgroup, NIVO+IPI provided OS benefit vs anti–PD-1 (HR, 0.43; 95% CI, 0.28–0.64). In the BRAF-mutant subgroup, NIVO+IPI provided numerical OS benefit vs BRAFi/MEKi (HR, 0.64; 95% CI, 0.39–1.06). Additional clinical data and outcomes analysis will be presented; however, in this real-world study, patients with MBM who received NIVO+IPI had favorable outcomes regardless of BRAF status, although more follow-up is needed.