Blood form trypomastigotes of the Y and CL strains of Trypanosoma cruzi were tested for their ability to enter and infect mouse peritoneal macrophages. Both strains failed to enter macrophages in appreciable numbers, whereas metacyclic trypomastigotes purified from acellular cultures were ingested with ease. Macrophage parasitization was enhanced manyfold after the removal of an antiphagocytic substance by trypsinization. This occurred without modification of parasite viability. Opsonization with hyperimmune mouse serum also enhanced the uptake of blood form trypomastigotes by macrophages. This effect was mediated by the macrophage Fc receptor. The effects of serum and trypsinization were additive at high parasite:cell ratios. Neither trypsin-mediated nor antibody-dependent opsonization of the organisms modified the fate of either strain within resident macrophages. However, lymphokine-activated macrophages were capable of destroying both strains, and antibody opsonization further enhanced this process.