Topical silicone-gel sheeting has been shown to be beneficial in the treatment of established hypertrophic and keloid scars. Certain individuals and incisions in specific body sites appear to be at increased risk for the development of such scars. A simple, inexpensive, and preventive treatment in these individuals at increased risk could potentially minimize the extended period of pressure therapy and repeated steroid injections that are often required to optimize outcome. However, the effects of applying silicone-gel sheeting in the immediate postoperative period as a preventive measure have not been investigated to date. Because silicone-gel sheeting influences the remodeling and maturation phase of collagen formation, we believed it prudent to determine whether silicone-gel sheeting had any deleterious effect on early wound healing, as demonstrated by in vivo biomechanical testing of wound strength and histological assessment. To investigate the potential effects of silicone-gel sheeting on acute wound healing and its possible application for prevention of hypertrophic scars, a study was designed in the hairless guinea pig. In phase 1 of the study, bilateral dorsolateral incisions were made, allowing each guinea pig to serve as its own control. One wound was dressed with silicone-gel sheeting, and the control site was dressed with Nu-gauze dressing. Wounds were then assessed visually and with in vivo biomechanical analysis of wound strength at days 3, 5, and 7 postoperatively (n = 7 per group). Phase 2 of the study compared identical dressings in a similar animal model using a single dorsal midline incision, in which alternate halves of each wound served as the control. Each wound was assessed histologically at days 3, 7, and 14 (n = 5 per group). Despite an improved subjective appearance of those wounds treated with the silicone sheeting applied at the time of incision closure in the hairless guinea pig model, no significant adverse or beneficial effect on in vivo wound healing strength on days 3, 5, and 7 was demonstrated compared with controls when analyzed using a paired observation f-test (p= 0.35, 0.20, and 0.47, respectively). Blinded interpretation of histological specimens showed no difference on hematoxylin and eosin or trichrome staining between the test and control sites at any interval assessed in this study. We believe this information confirms the safety of applying silicone-gel sheeting at wound closure in this model and thus opens the door for subsequent clinical trials to assess the role of these products in preventing hypertrophic or keloid scars.