OBJECTIVES: Significant attention is being focused on reducing surgical site infections (SSI) in the US and numerous national initiatives have been put into place to achieve measurable reductions. The purpose of the study was to examine the economic impact of therapeutic antibiotic (TA) utilization as an indicator of postoperative SSI between two time periods. METHODS: Premier inpatient database was utilized for assessing length of stay (LOS) and costs. Two time periods identified, 2005-2008 (period 1) and 2009 (period 2) with 1,138,989 patients discharged in 2005-2008 and 305,073 discharged in 2009. The patients with non-SSI nosocomial infections were excluded. TA usage was determined by the antibiotic administration after day 4 of surgery (TA utilization rate: 0.61% in 2005-2008; 0.75% in 2009).  Multivariate analysis used to assess the effects of using TA on LOS and total costs outcomes. RESULTS: Patients receiving TA had significantly higher LOS and costs for both time periods (p<0.001). Average LOS for patients receiving TA was 12.2 and 12.6 for periods 1 and 2 respectively. Mean post-surgical LOS was 9.8 and 10.0. Patients not receiving TA had average LOS of 4.6 and 4.6 in periods 1 and 2 and mean post-surgical LOS was 3.9 and 3.8 for periods 1 and 2. Mean (SD) total costs for TA patients were significantly higher, $28,601 ($31,892) in period 1 and $32,751 ($38,194) in period 2, compared to $15,336 ($33,406) and $15,412 ($20,311) for patients not receiving TA. Predictors for significantly higher risk of TA use included General Surgery, Non-cardiac Thoracic procedures, bed-size under 500 or Rural, and Staples or Non-absorbable sutures usage. CONCLUSIONS: These findings suggest minimal impact on the SSI economic burden indicated by similar trends in antimicrobial utilization, costs and LOS over time.  Further studies are warranted assessing the role of innovative technology to improve patient outcomes while reducing antibiotic utilization and LOS.