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Hypertrophic scar (HS) is a fibroproliferative disorder that causes cosmetic as well as functional problems; however, to our knowledge, there is no satisfactory treatment for HS to date. Previous studies have indicated that angiogenesis plays a crucial role in HS formation; therefore, anti-angiogenetic therapies are considered effective in improving HS. Although tacrolimus (TAC) has been proven effective in preventing HS formation in vivo and in vitro, its underlying mechanism remains controversial and ambiguous. Because of its anti-angiogenic effects in other diseases, we aimed to determine whether TAC reduces HS by suppressing angiogenesis. Using a rabbit ear HS model that we developed, HS was treated once a week with normal saline, dimethyl sulfoxide, or TAC for 3 weeks. Histological evaluation indicated that TAC significantly reduced collagen deposition and microvessel density in scar tissues. Moreover, immunofluorescence staining for CD31 and vascular endothelial growth factor (VEGF)-A revealed that TAC significantly inhibited HS angiogenesis. In vitro analysis showed that TAC inhibited endothelial cell migration and tubulogenesis as well as the viability and proliferation of human umbilical vascular endothelial cells (HUVECs) and HS fibroblasts (HSFBs). Furthermore, TAC significantly downregulated the expression of the human angiogenetic factors VEGF-A, FGF-2, PDGF-β, and TGF-β1 in HUVECs and HSFBs. Additionally, TAC-mediated inhibition of angiogenesis decreased the gene expression of crucial fibrotic markers, including α- smooth muscle actin and collagens 1 and 3, in HSFBs. This is the first study to demonstrate the inhibitory effects of TAC on HS formation mediated by a mechanism involving the suppression of scar angiogenesis.