Peritoneal macrophages from mice infected with Trypanosoma brucei brucei expressed a greatly elevated procoagulant activity (PCA) which could be reversed to normal levels after trypanocidal therapy. Comparison with infection caused by the non-pathogenic T. musculi suggested that the level of PCA related to parasite pathogenicity. Unstimulated macrophages, which generate only slight PCA upon stimulation with zymosan, become hyperresponsive to this stimulus during the course of infection. Hyperresponsiveness is not a generalized feature of these cells during infection, as they become progressively hyporesponsive to the same stimulus in terms of lysosomal enzyme secretion. We were unable to demonstrate a direct role of the trypanosomes in macrophage activation; however, artificial removal of the glycoprotein coat rendered the parasites highly stimulatory for macrophages even in the absence of opsonins. These results suggest that the parasites may activate macrophages indirectly, and that the resulting elevated PCA may play a role in the abnormal blood coagulation known to occur in this disease.