Abstract Methods: Susceptible Balb/c and resistant C57Bl/6 mice were infected with Y strain T. cruzi. Parasitemia was monitored; plasma was collected and analyzed for specific and total antibody. T. cruzi specific responses were measured by reactivity to recombinant T. cruzi complement regulatory protein (CRP). In separate experiments, Balb/c and C57Bl/6 mice were immunized intradermally via particle bombardment (gene-gun) with plasmid DNA containing the CRP gene. Results: Experimentally infected mice increase total plasma immunoglobulin (IgM, IgG) prior to specific response. Development of T. cruzi specific IgG response was delayed in Balb/c mice compared to C57Bl/6 mice, with comparable parasitemia. After immunization, Balb/c mice generated a higher titer IgG response than C57Bl/6 mice. Conclusion: Experimental infection of mice with T. cruzi leads to an early increase in total plasma immunoglobulin levels, but a delayed antigen-specific response in Balb/c compared to C57Bl/6 mice. The lack of specific response early in infection in the Balb/c model was not due to an inherent inability to produce IgG in response to T. cruzi CRP antigen as these mice were more responsive to the CRP antigen in an immunization model. This suggests that the delayed T. cruzi specific response in Balb/c mice is a result of a host/pathogen interaction involving a polyclonal humoral response to the parasite.