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Background: The current healthcare and economic burden of venous thromboembolism (VTE) in US hospitals is significant. In patients with confirmed VTE, evidence-based guidelines recommend treatment for a minimum of 5 days with either low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH). However, the relative total hospital direct medical costs and VTE-related readmission rates of these regimens for VTE treatment in large real-world populations are, as yet, unresolved. Methods: This retrospective cohort analysis of discharge and billing records from the Premier Perspective™ database included discharges of patients ≥18 years old and with a primary diagnosis of VTE from January 2003 through June 2005. Discharges with prior VTE during the 12-month period prior to the index hospitalization or a pre-existing contraindication to anticoagulant therapy were excluded from the analyses. Total hospital direct medical costs associated with VTE treatment (including drug costs, hospital costs, and professional costs) were collected and compared for UFH and LMWH. Furthermore, VTE-related readmission rates at days 30 and 90 post-discharge were compared for each of these agents. Total direct medical costs (US $) were compared using generalized linear models (SAS 9.1 PROC GENMOD), adjusting for patient and hospital characteristics. Logistic regression was used to compare the likelihood of readmission within 30 and 90 days. Results: A total of 38,664 discharges surveyed met the inclusion criteria, 20,577 (53%) receiving LMWH and 18,087 (47%) receiving UFH. The two groups were broadly similar in clinical and demographic characteristics, although mean length of stay was 1.1 days longer in the UFH group (5.7 days [SD=2.9] vs. 4.6 days [SD=2.9] for LMWH, P Conclusion: In a large, real-world population of patients from across the United States, LMWH is associated with reduced total direct medical costs for the acute treatment of VTE when compared to UFH. This reduction occurs despite higher drug-related costs for LMWH. In addition, patients receiving LMWH are less likely to be readmitted to hospital within 90 days with recurrent VTE.