OBJECTIVE: Clinical trials have demonstrated the safety and efficacy of prophylaxis with unfractionated heparin (UFH) and low-molecular weight heparins such as enoxaparin against venous thromboembolism in acutely-ill medical inpatients. The objective of this study was to estimate the cost-effectiveness of these alternative methods of thromboprophylaxis in this population. METHODS: We used techniques of decision analysis and data from secondary sources to estimate the cost-effectiveness of thromboprophylaxis in acutely-ill medical inpatients. A hypothetical cohort of 10,000 patients was assumed to receive, alternatively, prophylaxis with: (1) enoxaparin 40 mg qd; (2) UFH 5,000 IU bid; (3) UFH 5,000 IU tid; or (4) no prophylaxis. For each strategy, we estimated the 30-day risks of thromboembolism (deep-vein thrombosis and/or pulmonary embolism), complications of prophylaxis and therapy (heparin-induced thrombocytopenia and bleeding), mortality, and costs of prophylaxis, diagnostic testing and treatment. Cost per death averted was assessed for each method of prophylaxis relative to no prophylaxis. A background mortality risk of 10% was assumed. RESULTS: In a cohort of 10,000 inpatients, expected numbers of deaths over 30 days were 1,041 for enoxaparin, 1,058 for UFH bid, 1,058 for UFH tid, and 1,089 for no prophylaxis. Corresponding estimates of the expected costs of prevention, diagnosis, and management of venous thromboembolism were $3,655,800, $3,750,400, $4,300,400, and $3,363,000 (2001 US$). Relative to no prophylaxis, the cost per death averted was $6,101 for enoxaparin, $12,498 for UFH bid, and $30,240 for UFH tid. Incremental analyses indicated that prophylaxis with enoxaparin is both more effective and less costly than UFH. These findings were robust with respect to changes in the background risk of thromboembolism and risk of death from competing causes. CONCLUSIONS: Thromboprophylaxis with enoxaparin represents a cost-effective use of health-care resources and dominates strategies involving the use of UFH in acutely-ill medical inpatients.