OBJECTIVES: To determine the overall and per episode direct inpatient cost burden of malignant mesothelioma in the United States.  METHODS: This cross-sectional study included patients in the U.S. National Inpatient Sample of the Healthcare Cost and Utilization Project (H-CUP) that were discharged from community hospitals with a primary diagnosis of malignant mesothelioma (MM).  Hospital charges were converted to costs using the charge-to-cost ratio file, and results were weighted to provide U.S. nationally representative estimates. Costs were adjusted to 2015 dollars using the medical inflation index.  Average per-episode costs were determined overall, and according to demographic, treatment and clinical characteristics. Descriptive statistics were used in presenting the mean cost and standard deviation (SD) for each estimate, and generalized linear models were employed to identify predictors of episode cost. RESULTS: In 2012 there were an estimated 2,055 hospital discharges having a primary diagnosis of malignant mesothelioma.  The total overall cost to the U.S. healthcare system in 2015 dollars was $50,473,622 (SD $568,854,575).  The average per-episode cost was $25,556 (SD $85,033; range $37 - $593,825. The average cost for episodes involving a major operating procedure was $30,734 (SD $12,090,114), versus $13,493 (SD $1,219,778) for episodes not involving a major operating procedure (p < 0.001). The average cost per-patient per-day was $4,021 (SD $41,094).  Of 37 variables included in the saturated generalized linear model, 13 were statistically significant for predicting cost; these included length of stay, episodes associated with a major operating procedure, U.S. demographic region, and various comorbidities. CONCLUSIONS: Malignant mesothelioma is a rare disease, and healthcare utilization and cost data are lacking. This analysis provides estimates of the U.S. inpatient cost burden associated with this disease which augment the published health economic data for this form of cancer.