The initial management of patients (pts) with advanced stage BRAF-mutated melanoma includes immuno-oncology (IO) and targeted (TT) therapy. An ongoing randomized trial is comparing these therapies (NCT02224781); real-world analysis may provide early insights. Electronic health records from 15 cancer centers (Cota observational database) were reviewed to identify pts with BRAF V600-mutated melanoma (excluding pts with prior adjuvant therapy or in a clinical trial). 104 BRAF-mutated pts received first-line therapy for metastatic (n=101) or unresectable (n=3) melanoma between Nov 2011-Nov 2017. Median age was 66 yr (61% male); 48 pts received IO and 56 TT. Median follow-up was 11 mo (range 1-61; IO=16 mo, TT=10 mo). Pts treated with IO and TT were similar in age, race, sex, academic and community setting, presence of symptoms, number of mets sites, and presence of brain mets. More pts on TT had liver mets (IO 17% vs TT 38%, p=0.03) and elevated LDH (IO 35% vs TT 57%, p=0.02). Median Kaplan-Meier estimated overall survival (OS) was higher with IO (IO=23 mo, TT=14 mo; log-rank p=0.03), with 1-yr survival rates of 76% for IO and 50% for TT. Among pts with low-risk characteristics (absence of symptoms p<0.01, no liver/brain mets p=0.02, <2 sites of mets p=0.04, normal LDH p=0.09), pts on IO had significantly improved OS compared with TT; no significant difference was found in pts with high-risk characteristics. After adjusting for differences in pt characteristics, pts on IO had a 47% reduced risk of death compared with TT (HR 0.53; p=0.03). This real-world analysis of pts with advanced stage BRAF-mutated melanoma provides an early insight that initial therapy with IO may result in improved OS. However, this retrospective study cannot control for time-related differences in drug availability and undefined variables of pt risk. Accrual to a randomized trial remains a priority.