Statement of the Problem: Keloids are benign hyperproliferative growths of cells and extracellular matrices (ECM) in response to cutaneous injury, and remain a clinical challenge with no single successful treatment modality. The excessive collagen accumulation represents a dysregulation of ECM proteases and protease inhibitors, such as urokinase-plasminogen activator and plasminogen activator inhibitor-1, and matrix metalloproteinases (MMPs) and their inhibitors. Imiquimod, an immune modulating medication, has been recently reported in several clinical series to prevent keloid recurrence. However, the mechanism of imiquimod-induced keloid suppression is not understood. The purpose of this study was to determine whether imiquimod has any effect on collagen synthesis in keloids using our established collagen embedded 3-dimensional skin explant system and the in vitro primary culture of keloid fibroblasts.