Background An antimicrobial stewardship program (ASP), aiming to optimize antimicrobial usage, was implemented at a Veterans Affairs Health Care System (VA HCS). Objective The main objective of this study was to compare antimicrobial usage before and after implementation of an ASP and to assess ASP interventions. Method This retrospective study was conducted at the Fargo VA HCS. A total of 1,017 inpatient charts were reviewed for 2 distinct time periods, February through September 2008 (pre ASP) and February through September 2010 (post ASP). The data that were collected and analyzed included the number of hospitalized patients prescribed antimicrobials, antimicrobial therapy duration, duration of hospital stay, and inpatient antimicrobial costs. Subgroup analyses were performed on the top 5 antimicrobials and the top 6 indications. The number, types of, and overall acceptance rate of ASP interventions were also assessed. Results When the pre- to post-ASP periods were compared, the percentage of patients on antimicrobial therapy decreased from 36.8% to 25% (P < .001), the median duration of antimicrobial therapy significantly decreased (P = .02), and the defined daily dose (DDD) per 1,000 patient bed days was reduced for piperacillin/tazobactam, vancomycin, and ciprofloxacin. In addition, the total inpatient antimicrobial costs decreased by $48,044 (25%). The overall ASP intervention acceptance rate was 81.6% (315 out of 386 total interventions). Conclusion The results of this study show that ASP implementation has been highly accepted by providers and has been associated with a reduction in the number of patients prescribed antimicrobials, median duration of antimicrobial therapy, and antimicrobial inpatient costs.