Chronic infection with Trypanosoma cruzi causes significant morbidity and mortality. The parasite expresses on its surface and sheds into the extracellular milieu a large superfamily of trans-sialidase proteins. Previous studies have demonstrated that during T. cruzi infection, the trans-sialidase superfamily stimulates an antibody response, but how individuals respond to different proteins of the trans-sialidase superfamily remain poorly defined. In this report, we present an analysis of the antibody response of chronically infected individuals and inbred strains of mice to a panel of 11 different trans-sialidase proteins encoded by surface antigen 85 kD (SA85-1) genes. These data indicate that: (1) 90% of the individuals tested generated antibodies to one or more trans-sialidase proteins; (2) the individuals develop different patterns of antibody responsiveness to the panel of trans-sialidase proteins; (3) three inbred strains of mice develop trans-sialidase antibody responses, but each strain develops a different pattern of antibody response to the panel of trans-sialidase proteins; (4) the differences in the pattern of antibody response by the mouse strains are independent of MHC differences; and (5) trans-sialidase proteins that do not stimulate an antibody response during T. cruzi infection can stimulate a response following immunization. Together these data indicate that during T. cruzi infection individuals develop a diverse trans-sialidase antibody response that appears to be affected by genetic and environmental factors.