It is becoming clear that immune responses are subject to modulation by the sympathetic nervous system. We examined the effect of chemical sympathectomy (to ablate peripheral sympathetic nerve fibers) on cytokine and Ab production in two strains of mice that are known to differ in their response to a variety of pathogens and in the dominant types of cytokines produced. C57Bl/6J mice produce a strong cell-mediated response, characterized by production of IL-2 and IFN-gamma, whereas BALB/cJ have a dominant humoral response, with production of IL-4 and IL-10. Animals were denervated by injection with 6-hydroxydopamine and immunized with keyhole limpet hemocyanin, and spleens were removed at various times after immunization. Denervation significantly increased the keyhole-limpet-hemocyanin-stimulated in vitro proliferation and IL-2 and IL-4 production by splenocytes from both strains. The increases were prevented by pretreatment with desipramine, which blocks the uptake of 6-hydroxydopamine into the nerve fibers and subsequent nerve fiber destruction. Serum titers of IgM, IgG, IgG1, and IgG2a were also enhanced in the C57Bl/6J strain; BALB/cJ mice had a small increase in IgG1 only. These results suggest that one function of splenic innervation and transmitter release may be to modulate T helper cytokines, thereby partially regulating immune effector function. Our evidence is consistent with a model of immune regulation in which removal of sympathetic nervous system input enhances at least some parameters of immune responses.