Neuropilin 1 (NRP1) is a co-receptor for vascular endothelial growth factor (VEGF(165)), an inducer of vascular permeability and angiogenesis. Numerous physiological factors enhance VEGF expression and function but only a few have been shown to be negative regulators. Previously, we have shown that the naturally occurring soluble form of NRP1 (sNRP1) inhibits binding of VEGF(165) to endothelial cells in vitro and impairs tumor growth in vivo. To investigate the role of sNRP1 in the regulation of vascular development and function, sNRP1 expression was targeted to the skin, where it is not normally expressed, using a keratin 14 (K14) promoter expression construct. K14-sNRP1 transgenic mice displayed normal skin architecture with a subtle abnormal vascular phenotype. While the overall number of skin blood vessels remained unchanged, the lumen size of smooth muscle-associated dermal vessels was reduced. K14-sNRP1 mice had reduced vascular permeability in response to VEGF(165), but also to VEGF(121) and platelet activating factor, suggesting that the lack of permeability was not solely due to the sequestration of VEGF. sNRP1 also reversed the increase in inflammation and edema induced by transgenic VEGF overexpression in cutaneous delayed-type hypersensitivity reactions. In summary, sNRP1 appears to primarily regulate vessel permeability while its effect on physiological angiogenesis is less evident in this model.