Background: Surgical site infection is a major postoperative complication after surgical procedures. The effectiveness of postoperative antimicrobial dressings in reducing surgical site infections is unclear and limited information is available on the efficacy of chlorhexidine gluconate (CHG)-impregnated postoperative dressings. Methods: A pilot study was conducted to examine the efficacy of an innovative CHG-impregnated postoperative dressing in reducing the burden of methicillin-resistant Staphylococcus aureus (MRSA) in an in vivo porcine, incisional-wound model. Sutured incisional wounds were contaminated with MRSA and then covered with a CHG wound dressing, a placebo control, or a nonantimicrobial gauze. The surviving MRSA population was quantitatively cultured 3 days postprocedure. Results: MRSA was not recovered from any of the 8 wounds that were treated with the CHG dressing (limit of detection, approximately 1.7 log 10 colony-forming units [cfu]/g tissue). In contrast, the average microbial recovery from wounds treated with the placebo dressing was 4.2 log 10 cfu/g and the average microbial recovery from wounds treated with the gauze dressing was 3.2 log 10 cfu/g. Conclusions: An innovative CHG dressing provided significant antimicrobial activity against MRSA contaminating a surgical wound in a porcine, incisional-wound model. Future clinical studies are needed to assess the efficacy of the CHG dressing to reduce the bacterial burden in postoperative wounds of surgical patients.