OBJECTIVES: MEDENOX, a multinational double-blind, placebo-controlled trial (n=1102) of venous thromboembolism (VTE) prophylaxis among hospitalized acutely ill medical patients revealed lower incidence of VTE among patients receiving enoxaparin 40 mg once daily for 6-14 days relative to placebo (5.5% versus 14.9% p<0.001). Conducted in Europe and Canada, the trial did not include a prospective economic component. The purpose of this study was to model the cost-effectiveness of VTE prophylaxis with enoxaparin in a U.S. healthcare environment from the payer perspective. METHODS: From a national sample of U.S. hospital summary bills, we extracted records (n=374,855) of discharges matching MEDENOX diagnostic/demographic characteristics (primary diagnoses acute infectious disease, acute respiratory failure, or heart failure; mean age 73 years). With these data we estimated a multivariate model of admission cost. Regression parameters were incorporated in a pharmacoeconomic model of hospital admission for patients treated with or without enoxaparin per the MEDENOX protocol. Using Monte Carlo simulation, the model projected cost of admission as a function of diagnosis, length of stay, VTE prophylaxis/no prophylaxis. Outcome measures included cost of admission, cost for VTE prophylaxis, and incremental prophylaxis cost per VTE avoided. Not included were potential downstream costs for inpatient or post-hospital VTE treatment. RESULTS: In base case analysis, VTE prophylaxis accounted for 1.5 percent of average cost of admission ($125 of $7974 total cost, 90% confidence interval $96-$224). Relative to no prophylaxis, the incremental cost per VTE avoided using enoxaparin was $1330±468. CONCLUSIONS: Acutely ill medical patients are at high risk of VTE with treatment costs ranging from approximately $2500 (outpatient) to $25,000 (inpatient). Chronic care for post-thrombotic syndrome, experienced in 20%-56% of deep vein thrombosis patients, further increases the cost burden. This analysis demonstrates that VTE prophylaxis with enoxaparin, in acutely ill medical patients, has economic in addition to clinical benefits.