OBJECTIVE: Because of the difficulty of early Venous Thromboembolism (VTE) diagnosis and the serious consequences of the disease, prophylaxis is routinely indicated in medical at-risk patients. This study examines the effect of VTE prophylaxis by examining rate of secondary diagnosis of VTE in myocardial infarction patients and its impact on overall costs of in-patient care in order to optimize drug prophylaxis. METHODS: An administrative database of 720,982 discharges containing ICD-9-CM coding and other data from hospitals across the US was analyzed. Study patients had a principal diagnosis of myocardial infarction, and were prescribed heparin or enoxaparin. Associations between age, gender, length of stay (LOS), number of secondary diagnoses (NSD), drug, in-hospital deaths, overall hospital costs, and incidence of VTE were studied using logistic regression. RESULTS: From 8694 patients who met the inclusion criteria, 35 patients (0.40%; two enoxaparin vs. 33 heparin) showed a secondary diagnosis of VTE. Overall mean hospital costs (p<0.0001; OR=2.685) were found to be significantly different between patients showing a secondary diagnosis of VTE ($30,617.4) and those who did not ($15,689.0). However, when significant clinical and demographic factors were controlled for like LOS (p<0.0001; OR=1.053), in-hospital deaths (p=0.0121; OR=3.099), NSD (p<0.0001; OR=1.410), and age (p=0.0027; OR=1.041), overall hospital costs were not found to be significantly different (p=0.4459; OR=1.255). In patients who showed a secondary diagnosis of VTE, heparin prescribed patients incurred higher mean overall hospital costs than enoxaparin patients; p<0.0001 ($31,799.6 vs. $11,112.1), possibly due to a longer LOS (11.4 days vs. 5.5 days). CONCLUSIONS: The most cost-effective strategy in this analysis was VTE prevention and enoxaparin was a cost-effective treatment choice. Rational and adequate VTE prophylaxis needs to be addressed along with further research on administrative database coding and documentation issues in order to more fully explore the application of these findings for a clinician.