Venous thromboembolism is a life-threatening complication in patients following major trauma. These patients are at increased risk of deep-vein thrombosis and pulmonary embolism. In the absence of a major contraindication, anticoagulant prophylaxis with either low-dose unfractionated heparin or low-molecular-weight heparin is recommended. The objectives of this study were to undertake a systematic review and critically evaluate published cost-effectiveness analyses of anticoagulant prophylaxis against deep-vein thrombosis following major trauma. The results of the identified studies varied significantly, from enoxaparin being the dominant strategy based on the cost-per-deep-vein thrombosis averted, to low-dose unfractionated heparin being the dominant strategy based on the cost per life-year gained. In general, the more comprehensive the model, the more favorable the results were towards low-dose unfractionated heparin.