Surgical wound infections are one of the leading causes of morbidity and mortality in surgical patients. We compared the effectiveness of antimicrobial incise drapes versus cyanoacrylate microbial sealant adhesive barrier in preventing skin flora contamination of surgical wounds in an animal model. Staphylococcus aureus in suspension was placed on fresh ovine skin across 60 circular marks of defined area: 20 circles were designated as controls, 20 were covered with antimicrobial incise drapes, and 20 were covered with cyanoacrylate. Incisions were made through the circles; swab cultures were taken, serially diluted after agitation, and cultured on blood agar plates. The number of colony forming units (CFUs) was then counted and compared between the samples from the two drapes. While there were no differences between antimicrobial incise-draped areas (108.3 ± 90 CFUs) and undraped controls (82.7 ± 93.3 CFUs), the cyanoacrylate-treated group demonstrated lower wound bed contamination (0.3 ± 0.6 CFUs) when compared to controls.