Hypertrophic scar following cutaneous wounding is the result of the body overproducing collagen, and it has been shown that the activation of the adenosine A(2A) receptor promotes tissue repair, wound healing, and extracellular matrix production. In this study, we explored the role of adenosine receptor in hypertrophic scarring in adenosine A(2A) receptor knockout mice models. Mechanical stress was applied to a healing wound to produce hypertrophic scars in adenosine A(2A) receptor knockout mice and wild-type controls. Total scar areas were evaluated after routine hematoxylin and eosin and picrosirius red staining and hydroxyproline content measured colorimetrically. Expression of transforming growth factor-β in scar tissues was measured using the Western blotting method. Compared with the wild-type control group, adenosine A(2A) receptor knockout mice showed significantly less thickness, smaller cross-sectional area, and significantly lower hydroxyproline levels and transforming growth factor-β levels. These results demonstrate that adenosine A(2A) receptors play an active role in the pathogenesis of dermal fibrosis and suggest a novel therapeutic target in the prevention and treatment of hypertrophic scarring.