OBJECTIVES: Current American College of Chest Physicians' guidelines recommend Venous Thromboembolism (VTE) prophylaxis for orthopedic patients. This study examines prophylactic therapy received by hospitalized orthopedic patients, rate of secondary diagnosis of VTE, and compares overall hospital costs by major cost-centers among enoxaparin and warfarin-treated patients in order to rationalize drug use. METHODS: An administrative database of 720,982 discharges containing ICD-9-CM coding and other data from hospitals across the U.S. was analyzed. Study patients were those whom underwent hip or knee replacement procedures, and were prescribed warfarin or enoxaparin. Length of stay (LOS), age, gender, number of diagnoses (ND), and in-hospital deaths were compared between warfarin and enoxaparin cohorts using independent t-tests and chi-squared analysis. Least-squares regression was used to compare overall hospital costs between the two cohorts, controlling for differences in variable distribution. RESULTS: From 9234 patients who met the inclusion criteria, 4972 patients (53.8%) were prescribed warfarin and 5727 (62.0%) were females. Overall rate of secondary diagnosis of VTE was 0.08% (seven of 9241 patients; two enoxaparin and five warfarin patients). Apart from LOS (p=0.8089), NSD (p=0.2421), and gender (p=0.4223), distribution of age (p<0.0001) and in-hospital deaths (p=0.0045) were found to be significantly different between the two cohorts. Overall mean hospital costs were found to be different (p<0.0001) ($11,723.3 for warfarin patients versus $11,963.9 for enoxaparin patients), after controlling for significant differences. Enoxaparin patients incurred higher Medical/Surgical supplies ($616.7) and drugs/pharmacy ($312.1) expenses, while warfarin patients incurred more on Operating-and-Recovery rooms ($766.4), Medical/Surgical acute units ($487.3), and Laboratory ($39.6). CONCLUSIONS: Overall rate of secondary diagnosis of VTE is very low for orthopedic patients given prophylaxis; however, warfarin prophylaxis showed a higher rate. Enoxaparin demonstrated a better clinical outcome, but warfarin was significantly less expensive. Further research is needed to reconcile the clinical versus financial outcome findings from these analyses.