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Loss of skin flaps due to deteriorated wound healing is a crucial clinical issue. Extracorporal shock wave therapy (ESWT) promotes flap healing by inducing angiogenesis and suppressing inflammation. The receptor for advanced glycation end-products (RAGEs) was identified to play a pivotal role in wound healing. However, to date, the role of RAGE in skin flaps and its interference with ESWT are unknown.Caudally pedicled musculocutanous skin flaps in RAGE−/− and wt mice were treated with low-dose extracorporal shock waves (s-RAGE−/−, s-wt) and analyzed for flap survival, histomorphologic studies, and immunohistochemistry during a 10-day period. Animals without ESWT served in each genotype as a control group (c-RAGE−/−, c-wt). Statistical analysis was carried out by repeated-measures analysis of variance.Flap necrosis was significantly reduced after ESWT in wt animals but increased in RAGE-deficient animals. Morphometric differences between the 4 groups were identified and showed a delayed wound healing with dysregulated inflammatory cells and deteriorated angiogenesis in RAGE−/− animals. Furthermore, spatial and temporal differences were observed.The RAGE controls inflammation and angiogenesis in flap healing. The protective effects of ESWT are dependent on intact RAGE signaling, which enables temporary targeted infiltration of immune cells and neoangiogenesis.