In this study the wound healing response of full-thickness skin defects was enhanced through the use of acidic fibroblast growth factor using a collagen scaffold. The objectives of this study were (1) to compare the facilitatory effects of acidic fibroblast growth factor on the cellular response (fibroblast, neutrophil, macrophage, epithelial), tissue response (angiogenesis, collagen) and mechanical properties in a healing wound; and (2) to determine the effect of a collagen scaffold on wound healing when compared with the control. Three 3 × 3 cm full-thickness defects were created on the dorsi of 15 New Zealand White rabbits. Each rabbit had a control (no treatment), collagen scaffold, and collagen scaffold with FGF-1 (100 μg/ cm2). All the wounds were covered with a transparent polyurethane dressing. There were three periods of study (1, 2, and 3 weeks) with five rabbits in each period. The volume fraction of the tissue and cells was histomorphometrically determined for each wound. The acidic fibroblast growth factor/collagen system showed promise in enhancing the healing process. Acidic fibroblast growth factor/collagen treatment increased angiogenesis, enhanced epithelialization, and reduced contraction rate over the control. A higher inflammatory response was indicated in the collagen scaffold treated group. Hence acidic fibroblast growth factor delivered through a collagen scaffold shows promise in future clinical applications.