This study revealed that the absence of histamine in histidine decarboxylase gene-knockout (HDC-/-) mice resulted in delayed cutaneous wound healing and that exogenously administered histamine compensated this process. With the overproduction of histamine in HDC gene-transgenic mice, the healing was accelerated compared to the HDC+/+ mice. These results indicate that histamine positively accelerated the cutaneous wound healing. Macrophage recruitment and angiogenesis at the wound edge were specifically impaired in HDC-/- mice, and histamine-treated wounds in HDC-/- mice demonstrated increased macrophage recruitment and angiogenesis. The amount of basic fibroblast growth factor (bFGF) in protein level at the wound edge was higher in HDC+/+ mice, especially on the 3rd and 5th day of wound healing compared to those in HDC-/- mice. Topically administered SU5402, a specific antagonist to fibroblast growth factor receptor-1 tyrosine kinase, to the wound surface suppressed the wound healing in HDC+/+ mice but not in HDC-/- mice. Moreover, SU5402 reduced macrophage recruitment and angiogenesis in HDC+/+ mice. From these observations, it was concluded that the accelerated wound-healing activity of histamine was mediated by the activity of bFGF, which leads to angiogenesis, and macrophage recruitment in the wound-healing process.