Several neuropeptides have recently been shown to affect various aspects of the inflammatory process. Among these, the neuropeptide substance P possesses a host of immune modifying actions, which include the enhancement of lymphocyte activity, macrophage function, and neutrophil chemotaxis. The role of substance P during inflamed states has, as yet, not been fully described. Here, in T. spiralis-infected mice, we parallel increased levels of substance P both locally, (the gut) and peripherally (serum) with decreased lymphocyte responsiveness. Upon the introduction of in vivo antisubstance P antibody during the infection, levels of substance P, gastrointestinal inflammation, and lymphocyte proliferation are significantly restored to baseline (noninfected) levels. These findings suggest that the neuropeptide substance P plays an important role in promoting inflammation. It also offers the basis for future pharmacological interventions.