Several lines of in vitro evidence suggest the potential role of IFN-γ in angiogenesis and collagen deposition, two crucial steps in the wound healing process. In this report, we examined the role of IFN-γ in the skin wound healing process utilizing WT and IFN-γ KO mice. In WT mice, excisional wounding induced IFN-γ mRNA and protein expression by infiltrating macrophages and T cells, with a concomitant enhancement of IL-12 and IL-18 gene expression. Compared with WT mice, IFN-γ KO mice exhibited an accelerated wound healing as evidenced by rapid wound closure and granulation tissue formation. Moreover, IFN-γ KO mice exhibited enhanced angiogenesis with augmented vascular endothelial growth factor mRNA expression in wound sites, compared with WT mice, despite a reduction in the infiltrating neutrophils, macrophages, and T cells. IFN-γ KO mice also exhibited accelerated collagen deposition with enhanced production of TGF-β1 protein in wound sites, compared with WT mice. Furthermore, the absence of IFN-γ augmented the TGF-β1-mediated signaling pathway, as evidenced by increases in the levels of total and phosphorylated Smad2 and a reciprocal decrease in the levels of Smad7. These results demonstrate that there is crosstalk between the IFN-γ/Stat1 and TGF-β1/Smad signaling pathways in the wound healing process.