Fibroproliferative scars are an important clinical problem, and yet the mechanisms that regulate scar formation remain poorly understood. This study explored the hypothesis that the epithelium has a critical role in dictating scar formation, and that these interactions differ in skin and mucosa. Paired skin and vaginal mucosal wounds on New Zealand white (NZW) rabbits diverged significantly; the cutaneous epithelium exhibited a greater and prolonged response to injury when compared with the mucosa. Microarray analysis of the injured epithelium was performed, and numerous factors were identified that were more strongly upregulated in skin, including several proinflammatory cytokines and profibrotic growth factors. Analysis of the underlying mesenchymal tissue demonstrated a fibrotic response in the dermis of the skin but not the mucosal lamina propria, in the absence of a connective tissue injury. To determine if the proinflammatory factors produced by the epidermis may have a role in dermal fibrosis, an IL-1 receptor antagonist was administered locally to healing skin wounds. In the NZW rabbit model, blockade of IL-1 signaling was effective in preventing hypertrophic scar formation. These results support the idea that soluble factors produced by the epithelium in response to injury may influence fibroblast behavior and regulate scar formation in vivo.