2625 Background: Immunotherapy is a fast growing class of cancer therapy. We evaluated the rates of immune-related adverse events (irAEs), healthcare utilization, and costs up to 1 year post-index among patients using monotherapy (PD-1/PD-L1 inhibitor) and combination therapy (PD-1/PD-L1 with CTLA-4 inhibitors). Methods: We reviewed claims from the HealthCore Integrated Research Database (HIRD), which contains commercially insured/Medicare Advantage members and captures clinical, utilization, and cost measures. We analyzed both the monotherapy (M) and combination therapy (C) cohorts focusing on members with ≥ 6 months of baseline continuous medical and pharmacy coverage. Descriptive and multi-variate analyses were performed. Results: The C cohort had 904 and M had 9,084 patients, with mean ages of 58 and 64 years, respectively. Prominent cancer types were melanoma for C and lung for M. The most common incident irAEs (%) for C vs. M were: endocrinopathies (27.7, 14.7), hepatitis (17.1, 7.7), nephritis (21.0, 14.0), neuropathy (6.6, 7.0), followed by colitis, dermatitis, and myocarditis. After adjustment, C therapy showed greater risk of all-cause inpatient admissions (OR 2.27, 95% CI 1.93, 2.66), all-cause emergency department (ED) visits (OR 1.55, 95% CI 1.33, 1.81) and irAE-related visits (See table). Mean adjusted all-cause cost difference for C vs M was +$43,747 (95% CI $38,440, $49,427). In age ≥65 subset, 222 received C and 4,208 received M. C therapy patients had more irAE-related hospitalizations (45.3% vs. 57.7%, p=0.0004). Costs were similar to the main cohort. Conclusions: C therapy showed greater incident irAE rates, increased utilization and medical costs compared to M therapy. Limitations include less precise ascertainment of irAEs in claims data and generalizability only to those with commercial or Medicare Advantage insurance. Our study highlights the increased toxicity and cost tradeoffs involved in choosing combination immunotherapy over monotherapy.[Table: see text]