Trypanosoma cruzi, the etiologic agent of Chagas' disease, expresses trans-sialidase, an enzyme able to direct transfer of sialyl residues among macromolecules. The enzyme is shed and can be detected in blood during the acute phase of the disease. Several alterations of the immune response and apoptosis of cellular components of the immune system are observed early in the infection. The possible involvement of bloodstream trans-sialidase on these events was analyzed here. The enzyme induced apoptosis in cells of the immune system in the spleen, thymus, and peripheral ganglia. Both natural and recombinant trans-sialidases induced apoptosis to a similar extent. No effect was detected when enzymatically inactive recombinant molecules were used. In dose-response assays, apoptosis was observed even when an amount of trans-sialidase was administered that was enzymatically undetectable in blood. These findings strongly suggest a role for sialic acid mobilization in T. cruzi-induced apoptosis of immune system cells.