Metabolic dysfunction-associated steatohepatitis (MASH; formerly nonalcoholic steatohepatitis) is the inflammatory form of metabolic dysfunction-associated steatotic liver disease (formerly nonalcoholic fatty liver disease). MASH is a progressive disease associated with increased risk for many hepatic and extra-hepatic complications such as cirrhosis, hepatocellular carcinoma, the requirement for liver transplantation, and cardiovascular (CV)-related and kidney-related complications. It is important to understand the clinical and economic burden of MASH. To assess and compare the clinical and economic burdens of MASH in adults with the non-MASH population in a real-world setting. This observational, retrospective study used the Healthcare Integrated Research Database (HIRD), which contains health care claims data for commercially insured and Medicare Advantage health plan members across the United States. All-cause, CV-related, and liver-related medical costs and health care resource utilization were evaluated in patients with at least 2 diagnoses of MASH during the patient identification period (October 1, 2016, to April 30, 2022) and compared with a non-MASH cohort 1:1 matched on age, Quan Charlson Comorbidity Index, region of residence, and health plan type and length of enrollment. Generalized linear regression with negative binomial and γ distribution models were used to compare health care resource utilization and medical costs, respectively, while controlling for confounders. Covariate-adjusted all-cause, CV-related, and liver-related hospitalization rate ratios and medical cost ratios were assessed and compared for the MASH and matched non-MASH cohorts. A total of 18,549 patients with MASH were compared with 18,549 matched patients in the non-MASH cohort. After adjusting for covariates, MASH was associated with significantly higher rates of hospitalization and higher medical costs compared with the non-MASH cohort. When compared with the non-MASH cohort, patients with MASH had 1.22 (95% CI = 1.15-1.30; P < 0.0001) times higher rates of all-cause hospitalization, 1.13 (95% CI = 1.03-1.24; P = 0.008) times higher rates of CV-related hospitalization, and 7.22 (95% CI = 4.91-10.61; P < 0.0001) times higher rates of liver-related hospitalization. Similarly, all-cause medical costs were 1.26 (95% CI = 1.22-1.30; P < 0.0001) times higher, CV-related medical costs were 1.66 (95% CI = 1.59-1.73; P < 0.0001) times higher, and liver-related medical costs were 7.79 (95% CI = 7.42-8.17; P < 0.0001) times higher among patients with MASH. Compared with those of the non-MASH cohort with similar age, Quan Charlson Comorbidity Index, health plan, region of residence, and duration of enrollment, patients with MASH had significantly higher all-cause, CV-related, and liver-related hospitalizations and medical costs.