In this paper, we show that, during infection with Trypanosoma cruzi, there is a dramatic shift in the content of macrophage-bearing I-region-associated antigens (Ia). The percentage of Ia-bearing macrophages in normal peritoneal exudate is about 10%. This number changes to 50 to 100% after T. cruzi infection. The Ia-bearing cells are typical macrophages. Experiments were done attempting to explain the change in the Ia-bearing macrophages. Part of the influx of Ia-positive macrophages is mediated by immune T cells. Furthermore, direct conversion of Ia-negative macrophages to Ia-positive by direct infestation with T. cruzi led to negative results. We speculate that such a dramatic change in the composition of the macrophage may be an important immunoregulatory event in trypanosomiasis inasmuch as Ia-positive cells are essential for most T-cell reactions.