Trypanosoma cruzi proteinases are very likely involved in host-cell invasion. Physiological plasma-proteinase inhibitors from the macroglobulin (MG) family, among them alpha-2-macroglobulin (A2M), are found in tissues and in the plasma of mammals. By complexing to all classes of proteinases, MGs inhibit their action on high-molecular-weight substrates. In vitro studies have shown that A2M impairs T. cruzi proteases and, consequently, the parasite's ability to invade host cells and enhances the phagocytic and microbicidal actions of resident macrophages against T. cruzi. To test the hypothesis of a putative "protective" effect for MG, we quantified it in BALB/cj mice during the course of an experimental T. cruzi infection, comparing a posteriori the levels in mice that died with those in animals that survived, which were considered as being susceptible and resistant to the infection, respectively. The results showed that surviving mice showed an increase in plasma concentrations of MG during the first few weeks after the infection, whereas the levels in mice that died during the acute phase did not differ significantly from those in non-infected mice. These findings and the previous in vitro data indicate a role for physiological proteinase inhibitors, particularly alpha-macroglobulins, in resistance to T. cruzi infection, whereby a balance between parasite proteases and host protease inhibitors may be crucial. MG may thus participate in the complex network of reactions involved in the early acute phase of the disease and contribute by conferring to the host an ability to survive the infection.