OBJECTIVES Fondaparinux was shown to be non-inferior to enoxaparin in treatment of deep vein thrombosis (DVT) in a clinical trial setting. Comparisons of outcomes between these agents for treatment of DVT or pulmonary embolism (PE) in a naturalistic setting are not known. Objective of this study was to evaluate real-world economic outcomes of fondaparinux vs. enoxaparin for inpatient treatment of venous thromboemolism (VTE). METHODS Retrospective analysis of discharge data from over 550 US acute care hospitals was conducted to evaluate and compare economic outcomes of patients receiving fondaparinux or enoxaparin for VTE treatment. Discharges containing ICD-9 diagnosis codes for VTE (DVT, PE or both) were included. Total hospital charges and index anticoagulant charges were captured for initial admission and any readmissions for VTE within 30-day follow-up. Demographic, clinical, and hospital descriptive measures were used to compare two treatment cohorts and to inform multivariate models. Expenditures in fondaparinux and enoxaparin cohorts were compared using a generalized linear methods (GLM) approach. RESULTS Fondaparinux patients (n=366) were younger (61 vs. 64, p<0.001) than enoxaparin patients (n=14,674) and had more severe illness profiles (APR DRG 3.18 vs. 3.07, p=0.024). Average unadjusted charges for initial admission across the two groups were $76,352. Adjusted difference in charges for initial admission between fondaparinux and enoxaparin was not statistically significant (difference=$574; p=0.906). Average unadjusted charges for overall study period including 30-day follow-up were $80,764. Adjusted difference in charges between two groups was not statistically significant (difference=$3,633; p=0.536). Charges for index anticoagulant during initial admission were $2233 for fondaparinux and $2497 for enoxaparin (p=0.108). After multivariate adjustment, this difference was significantly lower in favor of fondaparinux (difference=$409, p=0.001). CONCLUSIONS These real-world economic outcomes corroborate clinical trial findings supporting non-inferiority of fondaparinux compared to enoxaparin for VTE treatment, as measured by hospital charges. Further analyses of clinical outcomes in a naturalistic setting are warranted.