Background: In metastatic melanoma (MM) patients, nivolumab can be used as monotherapy or in combinations with ipilimumab. The combination therapy has been shown in a randomized clinical trial to provide survival benefit in BRAF mutant patients with an increased toxicity. Using real-world data, we evaluated the impact on overall survival and post-treatment hospitalizations of 1L nivo alone vs nivo+ipi. Methods: We performed a retrospective cohort study of 1L treatment of patients with MM between 1/2016 and 12/2020, utilizing administrative claims data from the Anthem Cancer Care Quality Program. Real-world overall survival (OS) was defined as time from diagnosis to death. A Cox model with inverse probability of treatment weighting (IPTW) was used to adjust for demographic and clinical features. Adjusted hazard ratios (aHR) were estimated using weighted Cox proportional hazards models. Results: Our cohort included 708 1L MM patients, of them 466 (66%) treated with nivo+ipi. There was no difference in BRAF status between the treatment groups. Patients treated with nivo+ipi were younger and had more evidence of brain and lung metastasis. Following adjustment, nivo treated had significant longer OS compared to the nivo+ipi treated (aHR: 1.73 (1.25-2.35), p = 8e-4). This difference mostly stems from increased mortality of the combo treated in the first 6 months. At 24-months, 58% of the combination therapy treated patients were alive compared to 74% in the monotherapy group (p = 0.0006). Survival benefit was only observed in BRAF WT patients. In V600E patients no survival difference was observed (aHR: 0.8 (0.4-1.6), p = 0.5). Patients treated with the combination therapy had 5-fold more hospitalizations during the first 90 days after the treatment start (46% vs 10%, p = 3e-22). Conclusions: Our retrospective cohort study demonstrated improved survival for the monotherapy in BRAF WT patients. Combination therapy was associated with significantly more treatment-related hospitalizations and deaths, mainly in the first 6 months. The increased early morbidity of the combo should be considered in treatment decision.