CD4+ T cells have been separated into two subsets, designated TH1 and TH2, based upon the repertoire of lymphokines that they produce following stimulation. We have analyzed the role of these T-cell subsets in two chronic parasitic infections, leishmaniasis and schistosomiasis. In both diseases, we found a strong association with TH1 stimulation and protection, and TH2 stimulation and immunopathology. In addition, certain parasite antigens appeared to be strongly linked with either TH1 or TH2 cell development. This led to the establishment of protective T-cell lines and clones in a L. major model, from which we identified a new candidate antigen for vaccination against Leishmania parasites. Moreover, we show that protection against L. major infection can be significantly augmented by coadministration of IFN-gamma with antigen, a lymphokine known to inhibit TH2 cell proliferation. In S. mansoni-infected mice, animals with a patent infection exhibit an overwhelming TH2 response, while animals protectively immunized with irradiated cercariae preferentially produce IFN-gamma, a lymphokine associated with TH1 cell stimulation. In addition, we show that ablation of schistosome-induced eosinophilia by in vivo anti-IL-5 monoclonal treatment fails to reduce the protection induced by irradiated cercariae. Similarly, anti-IL-5 treatment resulted in egg-induced granulomas nearly devoid of eosinophils, but only caused a marginal reduction in granuloma size. These results demonstrate that an understanding of the factors controlling TH1 and TH2 development will significantly facilitate the identification and development of vaccines for parasitic infections.