The effect of passive antibody transfer against infection with vector-borne, metacyclic forms of Trypanosoma cruzi, and possible mechanisms of immunologic lysis of these organisms, were examined in this work. Anti-T. cruzi antibodies from mice surviving an infection conferred marked protection against challenge with a lethal dose (2,000 organisms) of metacyclic flagellates isolated from the reduviid insect Rhodnius prolixus. In vitro lysis of these parasites by immune sera from mice or chronic chagasic patients was found to require complement (C) activity since the phenomenon was abrogated by heating the sera at 56°C, adding the C inactivator cobra venom factor or in the absence of divalent cations. The lytic activity was provided via the alternative pathway of C activation since it was readily demonstrable in the absence of calcium ions. The metacyclic trypanosomes were also killed by human lymphocytes, neutrophils and eosinophils in the presence of anti-T. cruzi antibodies. Minimal or insignificant cytotoxicity was afforded by the cells or the antibodies when tested separately. These results emphasize the beneficial role of the humoral immune response in host defense against challenge with the form of T. cruzi responsible for natural infections.