Neuropeptides exert a variety of modulatory effects on inflammatory cellular responses. In order to investigate further activities of these cytokines on mechanisms in inflammatory processes, we determined the ability of substance P to promote human fibroblast chemotaxis. Cell migration was measured by two different assay types in modified Boyden chambers. Substance P was found to be a potent chemoattractant for human fibroblasts in vitro, eliciting a concentration-dependent migratory response. In further investigations we tested the chemoattractant potency of the fragments substance P-(1-4) and substance P-(3-11). As only the C-terminal analog promoted migratory responses, we suggest that the chemotactic responsiveness is largely encoded by the C-terminus of the neuropeptide, which is known to be active on neurokinin receptors. Involvement of neurokinin receptors of type 1 in the chemotactic response to substance P was indicated by fibroblast migration toward optimal concentration of a selective NK1 receptor agonist but not a NK2 receptor agonist. The observed ability of human fibroblasts to respond chemotactically to substance P elucidated another proinflammatory activity of this neuropeptide.