We have examined immunological responses in the skin-draining lymph nodes (SLN) and lungs of mice during the 3 weeks after percutaneous exposure to attenuated larvae of Schistosoma mansoni. Cercariae irradiated with 20 krads (V20) were highly protective and sustained an increased number of CD4+ T cells in the SLN. On secondary exposure to schistosome antigen in vitro, these cells were capable of proliferating and secreting high levels of interferon-gamma (IFN-γ) and interleukin-3 (IL-3). However, in mice exposed to non-protective 80 krad-irradiated (V80) cercariae, secretion of these cytokines occurred early and only transiently. Significantly elevated numbers of CD4+ T lymphocytes were recoverable on Day 21 from the lungs of V20, but not V80 mice. These cells secreted high levels of IFN-γ and IL-3 in vitro, but not IL-2 and IL-4. Mice immunized intravenously with attenuated lung-stage schistosomula were not protected, despite having an elevated pulmonary lymphocyte population. Moreover these cells failed to secrete IFN-γ and IL-3. However, significant protection was achieved where exposure of mice to a combination of V80 cercariae and lung-stage schistosomula resulted in the recruitment of IFN-γ secreting cells to the lungs. We conclude that the success of the irradiated vaccine depends not only on the generation of a population of antigen specific T-helper cells in the SLN, but also recruitment of these cells to the lungs before challenge.