To examine the role of different immunoglobulin subclasses in the immune clearance of Trypanosoma cruzi, mice containing bloodstream trypomastigotes were injected intravenously with immune serum, IgG-depleted serum, or with the IgG1 or IgG2 fractions and the rate of removal of the parasites from circulation was determined. Using IgG concentrations similar to those found in the immune serum, the rate of clearance mediated by IgG2 was six-fold higher than that obtained with IgG1. This difference did not appear to be due to differences in antibody specificity, as Western blotting showed that each isotype recognized a similar set of antigens extracted from the parasite. However, the T. cruzi specific antibody content of the IgG2 was approximately five-fold higher than IgG1. When the dose of IgG was adjusted to equalize the antibody content, the clearance ability of the IgG1 and IgG2 was very similar. It is concluded that the two subclasses have a similar clearance ability.