The percentage of Ia antigen-bearing (Ia+) macrophages was significantly lower in mice infected with Trypanosoma rhodesiense than in normal controls. The degree of difference varied with the source of macrophages and time course of infection. The percentage of Ia+ macrophages isolated from spleens 10 days after infection was 71% of that in the controls, and depletion continued until Ia+ macrophages were almost undetectable 30 days after infection. The rate of depletion was slower in the peritoneal cavity. In contrast, Ia+ macrophages were not significantly depleted from the lymph nodes until 30 days after infection. The ability of macrophages from trypanosome-infected mice to present listerial antigen to sensitized T cells was significantly lower than in controls. Immune T cells had significantly less ability (43% of controls) to incorporate thymidine when exposed to splenic macrophages from infected mice during the early stage of disease. This loss of antigen presentation increased during the course of infection. Peritoneal macrophages also exhibited an early loss of ability to present antigen, but no significant decline occurred thereafter. No significant loss of antigen had occurred in the lymph node macrophages 10 days after infection, but during the later stages of the disease a significant loss was detected. Treatment of macrophages from infected and control mice with anti-Iab serum and complement inhibited their ability to present antigen. Our results demonstrate that Ia+ macrophages and their distribution can influence the ability of infected animals to process antigens and may therefore account in part for the immunosuppression observed in trypanosomiasis.