Aims This study aimed to assess and compare the health care resource utilization (HCRU) and medical cost of metabolic dysfunction-associated steatohepatitis (MASH) by disease severity based on Fibrosis-4 Index (FIB-4) score among US adults in a real-world setting. Materials and methods This observational cohort study used claims data from the Healthcare Integrated Research Database (HIRD) to compare all-cause, cardiovascular (CV)-related, and liver-related HCRU, including hospitalization, and medical costs stratified by FIB-4 score among patients with MASH (identified by International Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM] code K75.81). Hospitalization and medical costs were compared by FIB-4 score using generalized linear regression with negative binomial and gamma distribution models, respectively, while controlling for confounders. Results The cohort included a total of 5,104 patients with MASH and comprised 3,162, 1,343, and 599 patients with low, indeterminate, and high FIB-4 scores, respectively. All-cause hospitalization was significantly higher in the high FIB-4 cohort when compared with the low FIB-4 reference after covariate adjustment (rate ratio, 1.63; 95% CI, 1.32–2.02; p < .0001). CV-related hospitalization was similar across all cohorts; however, CV-related costs were 1.26 times higher (95% CI, 1.11–1.45; p < .001) in the indeterminate cohort and 2.15 times higher (95% CI, 1.77–2.62; p < .0001) in the high FIB-4 cohort when compared with the low FIB-4 cohort. Patients with indeterminate and high FIB-4 scores had 2.97 (95% CI, 1.78-4.95) and 12.08 (95% CI, 7.35–19.88) times the rate of liver-related hospitalization and were 3.68 (95% CI, 3.11–4.34) and 33.73 (95% CI, 27.39–41.55) times more likely to incur liver-related costs, respectively (p < .0001 for all). Limitations This claims-based analysis relied on diagnostic coding accuracy, which may not capture the presence of all diseases or all care received. Conclusions High and indeterminate FIB-4 scores were associated with significantly higher liver-related clinical and economic burdens than low FIB-4 scores among patients with MASH.