Mice and guinea pigs were immunized with adult and cercarial extracts prepared in different ways. Most animals responded by producing moderate to high levels of cytotoxic antibody; but no correlation with resistance to infection could be detected. Initial experiments with a 3M KCl extract and with cercarial exoantigen produced partial resistance; several attempts to reproduce those results failed. Mice immunized either by live or attenuated cercariae, while developing very low levels of cytotoxic antibody, were highly resistant to challenge infection. These results are discussed in terms of a failure to induce a cooperative immune mechanism required for the action of cytotoxic antibody. It is suggested that homocytotropic antibodies may play a “gatekeeper” role by initiating a reaction that promotes the translocation of serum cytotoxic antibodies and cells into the tissue surrounding the migrating schistosomules.