Background: Venous thromboembolism (VTE) is a complication following surgery. Low-molecular-weight heparin (LMWH) or direct oral anticoagulants (DOACs) are efficacious but come with inherent bleeding risk. Mechanical prophylaxis, such as intermittent pneumatic compression (IPC), does not induce bleeding but may be difficult to implement beyond the immediate post-operative period. This study compared the cost and quality-adjusted life years (QALYs) saved of commonly used VTE prophylaxis regimens after lower limb arthroplasty. Methods: A previously published cost-utility model considering major efficacy and safety endpoints was updated to estimate the 1-year cost-effectiveness of different VTE prophylaxis regimens. The VTE strategies assessed included apixaban, dabigatran, rivaroxaban, LMWH, IPC, IPC + LMWH and IPC + apixaban. Efficacy data were derived from studies in PubMed, and cost data came from the 2017 Australian AR-DRG and PBS pricing schemes. Results: Costs for VTE prophylaxis including treatment of its associated complications over the first year after surgery ranged from AUD 644 (IPC) to AUD 956 (rivaroxaban). Across 500 simulations, IPC was the cheapest measure in 73% of simulations. In 97% of simulations, a DOAC was associated with the highest resulting QALYs. Compared to IPC, apixaban was cost-effective in 76.4% of simulations and apixaban + IPC in 87.8% of simulations. For VTE events avoided, the DOACs and IPC were on par. LMWH and LMWH + IPC were negatively dominated. Conclusions: Apixaban, IPC or a sequential/simultaneous combination of both is currently the most cost-effective VTE prophylaxis regimens. The choice between them is best guided by the relative VTE and bleeding risks of individual patients.