Hypertrophic scars are a major clinical problem, yet there are few therapeutics available to prevent or treat scar formation. One of the oldest known and most effective treatments is occlusion with silicone gel. However, little is known about its mode of action. It is hypothesized that occlusion increases the hydration state of the epidermis, and that this affects the epidermal and dermal cell behavior. This study investigated this possibility. Using the rabbit hypertrophic scar model, we determined that occlusion increased the hydration state of the epidermis in a dose-dependent manner, and significantly reduced the scar hypertrophy. Quantitative reverse transcription-polymerase chain reaction and immunohistochemistry showed that occlusion altered keratinocyte behavior, including keratin expression. Furthermore, occlusion significantly decreased the epidermal expression of the profibrotic cytokine interleukin-1β and increased the epidermal expression of the antifibrotic cytokine tumor necrosis factor α. These alterations in the epidermal gene expression resulted in concomitant changes in the expression of the transforming growth factor-β family members by cells in the dermis, resulting in a decrease in profibrotic signaling within the dermis. In summary, the results of this study indicate that occlusive therapy was able to decrease dermal fibrosis by hydrating the epidermis and altering the pro- and antifibrotic signals produced following injury.