Abstract Catalytic antibodies represent an innate defense mechanism that allows a subset of antibodies to bind and then hydrolyze their targets, making these antibodies up 1000-fold more efficient than conventional immunoglobulins. Pathogens have evolved B-cell superantigens (BC-SAgs) as an immunevasion strategy designed to neutralize catalytic antibody activity. Exposure to BC-SAgs such as the Staphylococcus aureus extracellular fibrinogen binding protein (Efb) and the HIV gp120 glycoprotein decreased catalytic activity to these antigens, respectively. We describe for the first time the identification and characterization of a Trypanosoma cruzi BC-SAg (Tc24). Immunization with Tc24 in the presence of different adjuvants significantly decreased the ability of purified IgM to hydrolyze Tc24 compared hydrolysis rates observed for IgM purified from unimmunized controls. Infection with T. cruzi resulted in a similar decrease in catalytic activity. In both immunization and infection models, the dose (of either Tc24 or the number of T. cruzi used to infect mice) affected Tc24 hydrolysis rates. Analysis of IgMs purified from infected humans also demonstrated reduced hydrolysis of Tc24 compared to hydrolysis rates observed for IgM purified from uninfected individuals. These data suggest that Tc24 is a BC-SAg that may impact the host's defenses early in the infection process.