BACKGROUND: There is controversy regarding the most appropriate strategy to prevent venous thromboembolism following total joint arthroplasty. Our objective was to estimate the lifetime costs, quality-adjusted life-years (QALYs), and costs per QALY gained using low-molecular-weight heparin compared with low-dose aspirin for two weeks after total knee or total hip arthroplasty in patients with no history of venous thromboembolism. METHODS: We used a Markov cohort model with health states of healthy after surgery, no postphlebitic syndrome after venous thromboembolism, postphlebitic syndrome after venous thromboembolism, and survival after intracranial hemorrhage to compare treatment with low-molecular-weight heparin or aspirin (160 mg) for fourteen days after total knee arthroplasty or total hip arthroplasty in patients with an age of fifty-five, sixty, sixty-five, seventy, seventy-five, eighty, or eighty-five years. We estimated lifetime costs, QALYs gained, and costs per QALY gained for both strategies, and applied a cost-effectiveness threshold of $100,000 (2010 U.S. dollars) per QALY gained. RESULTS: For patients undergoing total hip arthroplasty at the ages of fifty-five and seventy years, costs per QALY gained for low-molecular-weight heparin compared with aspirin were $315,000 and $1.4 million, respectively. For those undergoing total hip arthroplasty at the age of eighty or eighty-five years, aspirin cost less and saved more QALYs than low-molecular-weight heparin. For patients undergoing total knee arthroplasty at the ages of fifty-five, seventy, and eighty-five years, costs per QALY gained with low-molecular-weight heparin were $36,000, $112,000, and $448,000, respectively. Probabilistic sensitivity analyses confirmed a low probability of low-molecular-weight heparin being cost-effective for patients undergoing total hip arthroplasty and for those with an age of eighty years or older undergoing total knee arthroplasty. For individuals younger than eighty years of age undergoing total knee arthroplasty, the cost-effectiveness of low-molecular-weight heparin compared with aspirin is uncertain. CONCLUSIONS: For patients with no history of venous thromboembolism, aspirin is a cost-effective choice for venous thromboembolism prophylaxis following total hip arthroplasty, but the preferred choice following total knee arthroplasty depends on age and is uncertain for those younger than eighty years old.