Trypanosoma cruzi, the causative agent of Chagas disease, is able to reproduce intracellularly in many host cell types while in the mammalian host. Although cellular immunity is known to be important in resistance to infection, the ability of immune cells to interfere with the completion of the intracellular growth cycle of T. cruzi has not been described. Using a tissue culture system to study the parasite growth cycle, we have found that spleen cells from infected mice are able to decrease the number of parasites released from infected fibroblasts. Spleen cells from mice infected for as few as 14 days and as long as 300 days display this inhibitory ability. Parasite egress from infected cells is inhibited by factor(s) released by immune cells during coculture with infected fibroblasts. Immune cell depletion studies indicate that the inhibitory activity requires the presence of both CD4 T cells and μ B cells. These results suggest a direct ability of immune cells to somehow interfere with the completion of the intracellular cycle, and this ability may play a role in control of this parasite.