Background Relatively little contemporary data are available that describe differences in acute heart failure (AHF) hospitalization expenditures as a function of patient and hospital characteristics, especially from a population-based investigation. This study aimed to evaluate factors associated with variations in hospital expenditures for AHF in the United States. Methods A cross-sectional analysis using discharge data from the 2011 Nationwide Inpatient Sample, Healthcare Cost and Utilization Project, was conducted. Discharges with primary International Classification of Diseases, Ninth Revision, Clinical Modification, diagnosis codes for AHF in adults were included. Costs were estimated by converting Nationwide Inpatient Sample charge data using the Healthcare Cost and Utilization Project Cost-to-Charge Ratio File. Discharges with highest (≥80th percentile) versus lowest (≤20th percentile) costs were compared for patient characteristics, hospital characteristics, utilization of procedures, and outcomes. Results Of the estimated 1 million AHF hospital discharges, the mean cost estimates were $10,775 per episode. Younger age, higher percentage of obesity, atrial fibrillation, pulmonary disease, fluid/electrolyte disturbances, renal insufficiency, and greater number of cardiac/noncardiac procedures were observed in stays with highest versus lowest costs. Highest-cost discharges were more likely to be observed in urban and teaching hospitals. Highest-cost AHF discharges also had 5 times longer length of stay, were 9 times more costly, and had higher in-hospital mortality (5.6% vs 3.5%) compared with discharges with lowest costs (all P ;lt). Conclusions Acute heart failure hospitalizations are costly. Expenditures vary markedly among AHF hospitalizations in the United States, with substantial differences in patient and hospital characteristics, procedures, and in-hospital outcomes among discharges with highest compared with lowest costs.