C57BL/6 mice vaccinated with irradiated cercariae of Schistosoma mansoni are highly resistant to challenge infection. To examine the role of T-helper (Th) activity in these vaccinated (V20) mice, cells from skin- and lung-draining lymph nodes (LN) and the spleen were cultured in vitro with soluble schistosomular antigen. Peak proliferation and release of T-cell growth factor (TCGF) by axillary LN cells on Day 5, and by mediastinal LN cells on Day 18, reflected the kinetics of parasite migration. High levels of interferon-gamma (IFN-γ) were detected and production was prolonged, particularly in the mediastinal LN. The majority of the above activity was ablated with anti-CD4 antibody. IFN-γ production by spleen cells increased, whilst proliferation and TCGF release remained low. Although levels of proliferation were similar, more IFN-γ was released by LN cells from V20 mice than by those from mice infected with normal parasites (NI). This difference in IFN-γ production was magnified by the greater number of cells in LN of V20 than NI mice. On Day 22 post-exposure, 24-fold more IFN-γ was produced per pair of axillary LN in the former group. LN cells from V20 mice produced interleukin (IL)-2 and IL-4, whereas those from NI mice released IL-2 but negligible IL-4. Greater quantities of IL-3 were secreted by cells from V20 than from NI mice. These results support the conclusion that IFN-γ producing memory Th cells, generated in the LN of V20 mice, play an important role in protective immunity against S. mansoni.