Non-B, non-T cells from spleen and bone marrow of naive mice produce IL-4 upon stimulation by plate-bound IgE or IgG2a in the presence of IL-3. Infection of mice with Nippostrongylus brasiliensis (Nb) or injection of anti-IgD antibodies, treatments known to cause striking polyclonal IgE responses, increase the number of splenic non-B, non-T cells and cause 10-30-fold increase in IL-4 production by a standard number of these cells. In Nb-infected mice, IL-4 producing non-B, non-T cells can be found in the lungs, a site through which Nb larvae migrate. Non-B, non-T cells from anti-IgD-injected mice produce IL-4 in response to anti-IgE antibodies, indicating that these cells have been sensitized in vivo with IgE and that crosslinkage of such IgE can lead to stimulation of lymphokine production. Similarly, non-B, non-T cells from Nb-infected mice produce IL-4 upon stimulation with Nb-antigen, indicating that antigen can also crosslink receptors on in vivo sensitized non-B, non-T cells and stimulate lymphokine production. The striking increases in the IL-4-producing capacity of the splenic non-B, non-T cell population in anti-IgD-injected and Nb-infected mice and the in vivo sensitization of these cells strongly suggests that they may have an important role in lymphokine production in helminthic infections and other situations marked by striking elevations of serum IgE levels.