Effective immunological resistance to challenge with trypomastigotes of Trypanosoma cruzi has been linked to antibodies which are specific for determinants on live, but not fixed, trypomastigotes. In man and mouse, these antibodies can be detected specifically by viable immunofluorescence (VIF) and complement mediated lysis (CML) assays. VIF/CML positive sera from chagasic patients or experimentally infected mice recognize the same trypomastigote specific surface polypeptides of apparent Mr 70-160 kDa. VIF/CML negative chagasic sera fail to react with polypeptides of Mr 120, 145 and 160 kDa, whereas negative mouse sera lack antibodies to the 160 kDa component alone. Taken together, these clinical and experimental data suggest that the 160 kDa polypeptide should be tested for its potential in immunoprophylaxis.