Trans-sialidase, an enzyme that transfers sialic acid among macromolecules, has been implicated in invasion of host cells by Trypanosoma cruzi, the agent of Chagas' disease. Most antibodies produced in natural and experimental infections are directed to the highly antigenic C-terminal domain (shed acute-phase antigen). These antibodies do not inhibit the trans-sialidase activity, which is present in the N-terminal domain of the molecule. Antibodies able to inhibit trans-sialidase in sera from human infections have been found. TIA (trans-sialidase inhibition assay) was positive in sera from patients with acute and chronic infections. Healthy and congenitally infected infants born to mothers with Chagas' disease were also TIA-positive, but the antibody titers diminished within months after birth or after treatment. Thus, antibodies neutralizing trans-sialidase are detectable in most forms of T. cruzi human infections, and TIA may be useful in the diagnosis of Chagas' disease.