OBJECTIVES: Venous thromboembolism (VTE) has been the focus of numerous recent healthcare policy changes and initiatives in the United States (US). Varied methods of VTE prophylaxis exist and guideline adherence is low; here the current economic burden of VTE is evaluated and the budget impact of different methods of VTE prophylaxis considered, given their differing efficacy and safety profiles. METHODS: A structured literature search of PubMed was performed, using Medical Subject Headings (MeSH) and title and abstract searches to identify literature specific to VTE and VTE prophylaxis published on or after January 1, 2012. Returned literature were uploaded to Sourcerer (Covalence Research) for duplicate detection and title and abstract screening. Screening was performed by two reviewers against pre-defined exclusion criteria. Budget impact analysis was via a Markov model in Microsoft Excel®, including health states of ‘no VTE’, ‘deep vein thrombosis (DVT)’, ‘pulmonary embolism (PE)’, ‘DVT and PE’, ‘death’, ‘previous VTE’, and ‘post-thrombotic syndrome’. Alongside this ran a Markov model including ‘no bleed’, ‘minor’, ‘major’, and ‘death’. RESULTS: Searches returned 1,123 articles on efficacy and safety of VTE prophylaxis and 636 articles on healthcare burden. The estimated cost of VTE in the US is $10 billion, with each episode estimated to cost between $9,407 and $28,353 for VTE and $11,486 to $19,901 for PE. Recurrent events incurred reported costs of up to $82,110 in combined inpatient and outpatient costs. Major bleeding related to VTE prophylaxis was also associated with high costs: $10,346 to $28,177. No substantial differences in cost were apparent between prophylaxis with low-molecular-weight heparin and intermittent pneumatic compression (IPC) but decreased bleeding with IPC resulted in IPC being cost saving in certain scenarios. CONCLUSIONS: VTE is a significant burden to healthcare provision in the US. Different methods of prophylaxis do not substantially alter budgets, but IPC may reduce costs.