Two different populations of mast cells, that is, mastocytoma cells (P815) that were maintained either in vitro or in vivo, and mast cells obtained by differentiation of bone marrow precursor cells (MMC) in conditioned medium, were used as effector cells in antibody-dependent cytotoxic reactions (ADCC) against bloodstream trypomastigotes (BT) of Trypanosoma cruzi. The assay consisted of incubating effector cells with parasites that had been previously sensitized with immune mouse sera, immune IgG isotypes, or with medium. After the incubation period, the number of live BT was assessed. It was found that (a) cytotoxicity is antibody dependent; (b) the main isotypes involved are IgG1, IgG2a, and IgG2b; (c) both types of mast cells (mastocytoma and MMC cells) are equally efficient in killing BT; (d) mastocytoma cells degranulated by pretreatment with compound 48/80 are still able to effect ADCC; (e) on optical microscope examination, large numbers of parasites were often seen attached to the cells, but only when anti-T. cruzi antibodies were present; and (f) on electron microscope examination, no integral or ruptured parasites were seen inside the cells. We conclude that both T dependent and T independent mast cells are capable of mediating ADCC by a mechanism that is probably not dependent on granule extrusion.