OBJECTIVES: Prophylaxis with a low molecular weight heparin (LMWH) such as enoxaparin or a low-dose unfractionated heparin (LDUH) in high risk medical and surgical patients is consistent with the recommendations made by the American College of Chest Physicians 8th Conference on Antithrombotic and Thrombolytic Therapy. Whilst these guidelines present strong evidence to support the use of prophylaxis to prevent venous thromboembolism (VTE), they are not always adhered to in clinical practice. The St Vincent’s Private Hospital VTE Prevention Project aimed to improve compliance with best practice prophylaxis in hospitalised patients. An audit of the rates of prophylaxis was conducted over a 12-month period as part of this project. The aim of this analysis was to determine whether the measures implemented as a result of the St Vincent’s project translated into cost savings and improved clinical outcomes. METHODS:  A decision-analytic model was constructed using audit data from 21,942 medical and surgical patients admitted to St Vincent’s who received either enoxaparin 40 mg daily, unfractionated heparin (UFH) three times daily (TID) or no prophylaxis. The rate of prophylaxis at baseline was compared with that at the end of the audit for each prophylaxis regimen. Clinical trial data was used to estimate the incidence of VTE (defined as deep vein thrombosis (DVT) and pulmonary embolism (PE)), and major bleeding. RESULTS: As a result of the measures introduced to improve adherence to best practice, we estimated 13 fewer deaths, 84 fewer symptomatic DVTs, 19 fewer symptomatic PEs and 512 fewer hospital bed days over baseline, across all medical and surgical patients. We also estimated that overall costs were reduced by $245,439 over 12 months. CONCLUSIONS: Improved adherence to best practice in VTE prophylaxis in the Australian clinical setting is likely to result in fewer deaths, VTE events and significant overall cost savings.