Clinically and economically, venous thromboembolic (VTE) disease represents a significant burden to the US healthcare system. This analysis compares the total direct medical costs associated with VTE prophylaxis with enoxaparin and unfractionated heparin (UFH). Hospital discharge and billing records were extracted from the Premier Perspective database (January 2002-December 2006). The primary outcome was the total direct medical costs for discharges that were at risk of VTE and received enoxaparin or UFH. A total of 894,364 discharge records met the study inclusion criteria, of which 39.4% received enoxaparin and 60.6% received UFH. After adjustment for pre-defined covariates, mean total direct medical costs per discharge for the UFH group were $6,443, $1,080 more than those for the enoxaparin group ($5,363; P < .0001). In conclusion, enoxaparin prophylaxis is a cost-saving therapy, when compared with UFH, for the prevention of VTE in patients with a diverse range of medical conditions conferring VTE risk.