We have investigated the nature of the ligand involved in antibody-dependent cellular cytotoxicity (ADCC) of human leukocytes to epimastigotes of Trypanosoma cruzi. Purified anti-T. cruzi IgG was highly efficient in mediating ADCC whereas IgM mediated the killing of this parasite poorly even at high concentrations. The presence of the Fc portion on the IgG molecule seems to be necessary since F(ab')2 derived from anti-T. cruzi IgG did not mediate ADCC. We also present evidence suggesting that the mediator, aside from promoting the interaction between the effector and target cells, may play a functional role in triggering target destructions by the effector cells. This conclusion is based on results of experiments in which lectins capable of binding to both leukocytes and parasite were used as mediators of cellular cytotoxicity. The lectin concanavalin A could readily replace IgG for human leukocyte killing of T. cruzi. In contrast, lectins from Lens culinaris, Triticum vulgaris, Aaptos papillata and Bandeirae simplicifolia although capable of interacting with leukocytes and T. cruzi, did not mediate the cellular cytotoxicity of the parasites. The specific cellular mechanism of parasite killing, i.e. phagocytosis and or extracellular lysis, remains to be determined.