In order to study the role of FcgammaRs in Trypanosoma cruzi infection in mice, the 2.4G2 monoclonal antibody (MAb), specific to the extracellular domains of FcgammaRII and FcgammaRIII, was injected intraperitoneally into mice. Flow cytometry studies of uninfected mice showed that 2.4G2 MAb bound to peritoneal and lymph node cells, respectively, on days 2 and 6 after injection. Repeating 2.4G2 injections every 3 to 4 days decreased the availability of FcgammaRs on peritoneal, lymph node, and spleen cells. Injections of 2.4G2 MAb into T. cruzi-infected mice, at days - 1, 3, 7, 11, 16, 20, and 24 relative to infection, reduced mortality in comparison with that in infected animals injected with an unrelated MAb (50 versus 93.3% mortality; P < 0.01). Parasitemia in 2.4G2-treated mice was significantly (three times) lower than in control animals on days 21 and 24 postinfection (P < 0.05), before parasite-specific antibodies were detectable at significant levels. Immunoglobulin and T. cruzi-specific antibody levels were similar in all groups of mice. These results indicate that repeated injections of 2.4G2 MAb administered to acutely infected mice reduce the in vivo infection level, suggesting that FcgammaRs play a role in the early host invasion by T. cruzi parasites.