Objective: The estimated annual incidence of venous thromboembolism (VTE) is 5–12 per 10,000 and ~10% of hospital deaths are attributable to pulmonary embolism (PE). Despite prophylaxis, 1–3% of patients undergoing major orthopaedic surgery (MOS) develop symptomatic deep vein thrombosis (DVT). The incidence of recurrent VTE (DVT and PE) is ~20% and 33–50% of patients develop post-thrombotic syndrome (PTS). Despite the extensive healthcare burden of VTE, there is no systematic review of the associated costs. The objective of this study was to estimate the costs of VTE in the general population, and in patients undergoing MOS. Methods: A systematic literature review was performed, which focused on “all-cause” VTE and VTE following MOS. Included studies had to identify and measure, in clinical practice, health care utilization and the economic consequences of VTE and associated complications, including recurrent VTE, PTS and bleeding events. Results: Annual costs per patient for all-cause VTE were $10,804–33,200 in the US and ~€4000 in Europe. Following MOS, annual treatment costs per patient for VTE were €8265 in Europe. In the US, charges for the surgical admission were $52,037 for patients with VTE compared to $34,485 for those without. Complications associated with VTE and its treatment, described above, were frequent. Following MOS, the 1-year cumulative incidence of recurrent DVT was ~24%, ~6.5% for PE, with additional annual treatment costs in the US of up to $6400. European studies suggest that, despite the low cost of prophylaxis, the overall costs of VTE are approximately half the costs associated with MOS. The main cost drivers were inpatient care and hospitalization for recurrent events. Conclusion: VTE occurs frequently and is a major cost and resource burden for health care systems, particularly after MOS. Prophylaxis regimens that can reduce the incidence of VTE might enable significant cost savings to be achieved.