Background Mast cells (MCs) and nerves can induce cutaneous inflammatory responses, both independently and by interacting with each other. However, little is known about the role of skin nerves and neuropeptides in the regulation of MC-mediated skin inflammation, and the contribution of MCs in neurogenic inflammation is still controversial. Objective The aim of this study was to investigate the effects of cutaneous sensory nerves on MC-driven inflammatory responses. Methods Passive cutaneous anaphylaxis, a model for type I allergic skin responses, was studied in the presence or absence of sensory nerves by using a murine model of selective cutaneous denervation. Results Passive cutaneous anaphylaxis was significantly impaired in the absence of sensory nerves. This effect was not a result of an alteration of mast cell numbers in denervated skin. Moreover, IgE-mediated activation of mast cells was markedly decreased in denervated compared with normal skin. Notably, pretreatment of mice with selective antagonists of the neuropeptides substance P and/or calcitonin gene-related peptide also resulted in decreased inflammatory responses after MC activation. Conclusion These data suggest that sensory skin nerves augment MC-driven inflammatory responses by releasing neuropeptides that increase MC degranulation.