The purpose of this study was to compare two negative-pressure wound healing systems (NPWT), −75 mmHg with a silicone-coated (SC) dressing and −125 mmHg with polyurethane foam dressing (standard of care). In addition, this study compared the effects of two different dressing interfaces, SC dressing and gauze, with −75 mmHg pressure. For both comparisons, two groups of five pigs were evaluated over a 21-day time course. Two excisional wounds were made on each animal and NPWT dressings were applied. A canvas saddle was constructed to hold the NPWT device so the animal had free range of the pen. Dressings were changed twice a week and wound measurements were taken. Specimens for histology and gene expression analyses were taken on day 7 and 21. These data show that there is increased expression in a few genes associated with remodeling and inflammatory processes in the NPWT-125 with polyurethane foam as compared with the NPWT-75 with SC dressing. These two systems, however, are equivalent with respect to wound healing, histology, and gene expression over 21 days of healing. Further, we demonstrate that there is no difference in measure of healing between the SC dressing and a basic gauze dressing.