Wound healing is mediated through complex interactions between circulating immune cells and local epithelial and endothelial cells. Elements of the innate immune system are triggered when Toll-like receptors (TLR) are stimulated by their cognate ligands, and previous studies suggest that such interactions can accelerate wound healing. This work examines the effect of treating excisional skin biopsies with immunostimulatory CpG oligodeoxynucleotides (ODN) that trigger via TLR9. Results indicate that CpG (but not control) ODN accelerate wound closure and reduce the total wound area exposed over time by >40% (p<0.01). TLR9 knockout mice, a strain unresponsive to the immunomodulatory effects of CpG stimulation, are unresponsive to ODN treatment and exhibit a general delay in healing when compared with wild-type mice. CpG ODN administration promoted the influx of macrophages to the wound site and increased the production of vascular endothelial growth factor, expediting neovascularization of the wound bed (p<0.01 for both parameters). Stimulation via TLR9 thus represents a novel strategy to accelerate wound healing.