OBJECTIVE: To estimate the cost-effectiveness of low-molecular-weight heparin (LMWH) in the treatment of proximal lower extremity deep venous thrombosis. DESIGN: Cost-effectiveness analysis that includes the treatment of the index case and simulated 3-month follow-up. SETTING: Acute care facility. PATIENTS AND PARTICIPANTS: Hypothetical cohorts of 1,000 patients who present with proximal deep venous thrombosis. INTERVENTIONS: Intravenous unfractionated heparin (UH), LMWH (40% at home, 60% in hospital), or selective UH/LMWH (UH for hospitalized patients and LMWH for patients treated at home). MEASUREMENTS AND MAIN RESULTS: The outcomes were recurrent thrombosis, mortality, direct medical costs, and marginal cost-effectiveness ratios from the payer's perspective. At the base-case and under most assumptions in the sensitivity analysis, the LMWH and the selective UH/LMWH strategies dominate the UH strategy i.e., they result in fewer cases of recurrent thrombosis and fewer deaths, and they save resources. The savings occur primarily by decreasing the length of stay. The LMWH strategy resulted in lower costs as compared with the UH strategy when the proportion of patients treated at home was more than 14%. Treating 1,000 patients with the LMWH strategy as compared with the UH/LMWH strategy would result in 10 fewer cases of recurrent thrombosis, 1.2 fewer deaths, at an additional cost of $96,822; the cost-effectiveness ratio was $9,667 and $80,685 per recurrent thrombosis or death prevented, respectively. CONCLUSIONS: Treatment with LMWH leads to savings and better outcomes as compared with UH in patients with lower extremity deep venous thrombosis. The selective UH/LMWH strategy is an alternative option.