The aim of the present study was to experimentally evaluate whether topical fibrin-mediated administration of a vascular endothelial growth factor (VEGF)-A plasmid to the wound bed can protect skin flaps from necrosis. A plasmid expression vector containing the VEGF-A cDNA was constructed. The plasmid was then administered to the wound bed of rat abdominal skin flaps in a fibrin sealant. The percentage of viable, ischemic and necrotic tissue was assessed postoperatively as a baseline and after 3 and 7 days using digital surface area morphometry. Laser Doppler imaging of the flaps and VEGF-A Western blot analysis of flap tissue were performed to assess angiogenesis and VEGF-A tissue levels. Flaps treated with VEGF plasmids in the presence of uptake enhancing Lipofectamine transfection reagent increased flap survival 7 days postoperatively significantly associated with markedly elevated tissue perfusion and enhanced tissue VEGF-A protein expression. Our results indicate that topical fibrin-mediated administration of a VEGF-A plasmid may serve as an alternative to previous strategies in treating ischemic skin flaps. The suggested therapeutic approach is easily applicable and inexpensive in preparation. Thus, this protocol may also enhance wound healing in posttrauma skin lacerations or in skin grafts.