Background: Both pembrolizumab (PEMBRO) and ipilimumab + nivolumab (IPI + NIVO) are FDA-approved immunotherapy regimens for advanced melanoma (AM). Each regimen has different toxicity profiles potentially impacting healthcare resource utilization (HCRU). This study compared real-world hospitalization and emergency department (ED) utilization within 12 months of therapy initiation of each regimen.Methods: A retrospective cohort study was conducted in AM patients ≥18 years old initiating PEMBRO or IPI + NIVO between January 1, 2016-December 30, 2017. Patients were identified from 12 US-based academic and satellite centers. All-cause hospitalization ED visits were identified. These events were used to calculate rates per 1,000 patient months. Utilization between groups was compared using multivariate logistic regression.Results: In total, 400 patients were included (200 PEMBRO, 200 IPI + NIVO). PEMBRO vs IPI + NIVO patients had poorer Eastern Cooperative Group (ECOG) performance status, 29% 2-4, vs 12% (p < .001); more diabetes, 21% vs 13% (p = .045); were more often PD-L1 expression positive, 77% vs 63% (p = .011); and less likely BRAF mutant, 35% vs 50% (p = .003). The proportion with more than one hospitalization over 12 months was 17% PEMBRO vs 24% IPI + NIVO. Less than 2% had more than one admission and none had more than two. Unadjusted mean (SD) hospitalizations per 1,000 patient-months were 16 (37) and 20 (38), PEMBRO and IPI + NIVO, respectively. Adjusted odds ratio for hospitalization was 0.6 (95% CI = 0.3-0.9; p = .027) for PEMBRO vs IPI + NIVO. ED visits occurred in 18% vs 21%, PEMBRO and IPI + NIVO, respectively, 0.7 (p = .186).Conclusions: PEMBRO patients had a significantly lower probability of hospitalization through 12 months vs IPI + NIVO. The probability of ED visits did not differ.