The development of T cell reactivity toward schistosomula during murine Schistosoma mansoni infection has been studied using an adaptation of the in vitro lymphocyte proliferation assay in which the response is elicited by exposure to living schistosomula. The reactivity measured in this system was shown to be a T lymphocyte function and to require the presence of adherent cells. This assay may therefore provide a new method for analysis of basic interactions between host cells and schistosomula. Lymph node cell responses were observed in two phases, the first of which appeared during the second week after infection, reflecting the immunogenicity of schistosome larval forms. A later, more pronounced response appeared during the chronic stage of infection, where sensitization appeared to be stimulated primarily by ongoing exposure to adult worms, rather than eggs. Lung-stage and skin-stage larvae elicited a similar degree of thymidine uptake by cells from chronically infected mice. Intact skin-stage larvae and particulate fractions provoked greater proliferation than soluble larval constituents, indicating that the lymphocyte response is directed in large part toward determinants which remain associated with the schistosomula during culture. However, the presence of major histocompatibility complex products on the membrane of lung-stage schistosomula did not influence the presentation of larval antigens to sensitized lymphocytes. The implications of these findings in immunity to schistosomiasis are discussed.