Transforming growth factor (TGF)-β1 plays a central role in wound healing. Wounds treated with neutralizing antibody to TGF-β1 have a lower inflammatory response, reduced early extracellular matrix deposition, and reduced later cutaneous scarring, indicating the importance of local tissue TGF-β1. By contrast, increasing the local, tissue levels of TGF-β1 increases the early extracellular matrix deposition but does not alter scar formation. Increased levels of plasma TGF-β1 correlate with increased fibrogenesis in the lung, kidneys, and liver. The aim of the present study was to investigate the role of elevated systemic levels of TGF-β1 on wound healing. We used transgenic mice that express high levels of active TGF-β1 and have elevated plasma levels of TGF-β1 and wild-type mice of the same strain as controls. Incisional wounds and subcutaneously implanted polyvinyl alcohol (PVA) sponges were analyzed. Surprisingly, cutaneous wounds in transgenic, TGF-β1-overexpressing mice healed with reduced scarring accompanied by an increase in the immunostaining for TGF-β3 and TGF-β-receptor RII and a decrease in immunostaining for TGF-β1 compared with wounds in control mice. By contrast, the PVA sponges showed the opposite response, with PVA sponges from transgenic mice demonstrating an enhanced rate of cellular influx and matrix deposition into the sponges accompanied by an increase in the immunostaining for all three TGF-β isoforms and their receptors compared with PVA sponges from control mice. Together, the data demonstrate that increased circulating levels of TGF-β1 do not always result in increased expression or activity in selected target tissues such as the skin. The two wound models, subcutaneously implanted PVA sponges and cutaneous incisional wounds, differ significantly in terms of host response patterns. Finally, the data reinforce our previous observations that the relative ratios of the three TGF-β isoforms is critical for control of scarring.