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Background Fibrin sealant is an effective hemostatic agent and a useful tissue sealant. Studies have also suggested that fibrin sealant may accelerate the normal wound-healing process. Objective This study was designed to ascertain whether fibrin sealant would enhance wound healing after CO2 laser resurfacing in a guinea pig model. Methods The CO2 laser was used to create equal areas of skin resurfacing on both sides of 14 Dunkin Hartley guinea pigs. Fibrin sealant was applied to the treatment side, whereas bacitracin was applied to the control side. Biopsies of these areas were performed on days 1, 3, 7, and 10. A histologic evaluation was performed with the use of a grading scale that compared acute and chronic inflammation, granulation tissue, collagen deposition, and epidermal regeneration. Results The wounds treated with fibrin sealant demonstrated a statistically significant reduction in the degree of acute and chronic inflammation as well as collagen deposition. At day 7, fibrin sealant was noted to enhance neovascularization and result in a slight delay in reepithelialization. All wounds were completely reepithelialized at day 10. No wound infections or other complications were noted as a result of the application of fibrin sealant. Conclusions Although wound healing was not accelerated, the application of fibrin sealant after CO2 laser resurfacing diminished the acute and chronic inflammatory response, enhanced neovascularization, and reduced collagen accumulation. Further research is needed to assess whether the effects of fibrin sealant noted in this study result in improved cosmetic healing after CO2 laser resurfacing.