The interactions of Trypanosoma cruzi with L-cells, and with normal and activated macrophages in vitro were studied by ultrastructural techniques. T. cruzi actively invades cultured L-cells and uniformly destroys them. Normal macrophages could control a 1:1 (parasite to host cell) infection, but were destroyed by a 10:1 infection. BCG-activated macrophages, however, controlled a 10:1 infection but not one at a ratio of 100:1. It appears that parasites that survive within host cells do so outside cytoplasmic vacuoles, whereas when they are relegated to host cell phagosomes they are destroyed. Culture forms of T. cruzi have several means of access into host cells. Macrophages are better able to survive infection than are non-phagocytic cells. Finally, it is suggested that control of an experimental infection in vitro is dependent upon numbers of parasites to macrophages as well as the state of the macrophages.