Background: Melanoma brain metastases (MBM) are a common endpoint among patients with advanced melanoma and prognosis is poor. Strategies for MBM prevention can prolong life and reduce morbidity. Dual agent immunotherapy (dIT) has been paradigm-changing in management malignant melanoma management. Recent clinical trials have supported the role of dIT for upfront management of small, asymptomatic MBM. Yet, its potential role in extending brain metastasis-free survival (BMFS) and decreasing MBM incidence overall has not been explored. The objective was to compare MBM incidence, median overall survival (OS), and BMFS in melanoma patients treated with dIT versus single immunotherapy (sIT). Methods: A real-world deidentified database collating clinical information from 92 organizations (TriNetX, Inc.) was queried. Melanoma patients without brain metastases prior to immunotherapy were stratified by treatment (anti-CTLA4 [sIT] and combination anti-CTLA4/ anti-PD1 [dIT]) and propensity-score matched. MBM incidence was measured within 5 years post-IT initiation. A complementary single-institution retrospective cohort study analyzed melanoma patients treated from 2012-2019. Median OS and BMFS were compared via log-rank tests and multivariate Cox proportional-hazards models. A competing risk analysis was performed to measure the cumulative incidences of MBM and death without MBM. Results: TriNetX identified 8,686 melanoma patients who received immunotherapy (4,585 dIT; 4,101 sIT). MBM incidence was 13.4%, and 19.3%, for the dIT and sIT cohorts, respectively (p < 0.0001). DIT was associated with a lower likelihood of developing MBM compared to sIT (RR [95%CI], 0.69 [0.62-0.77]). After propensity-score matching on demographics and comorbidities, MBM incidence was similarly 13.3% and 18.5% for the dIT and sIT cohorts, respectively. On single-institution analysis, 130 melanoma patients were included (87 dIT; 43 sIT with anti-CTLA4). In patients with stage IV disease, median OS was 1.70 and 3.66 years for the sIT and dIT cohorts, respectively (p=0.6). Median BMFS was 1.56 and 2.36 years in the sIT and dIT cohorts respectively (p=0.76). On multivariable Cox proportional hazard regression analysis, NRAS mutation was significantly correlated with a worse prognosis for BMFS. Conclusions: These data highlight the impact of combination anti-CTL4/ anti-PD1 immunotherapy in decreasing MBM incidence. The potential primary prophylactic role of dIT in MBM warrants prospective exploration, including mechanistic understanding.