Survival of acute Trypanosoma cruzi infection by mice is influenced by genes inside and outside the major histocompatibility complex (MHC) and genes associated with resistance must be expressed in both the MHC and the genetic background or the host will die within a few weeks of infection. Both the levels and the kinetics of cytokine production have also been implicated as important factors for resistance. Antigen-stimulated spleen cells from mice that express the resistant H-2(q) MHC haplotype produced significantly more interferon(IFN)-gamma than did cells from mice that share the susceptible H-2(k) haplotype. But, spleen cells from susceptible and resistant mice produce similar levels of IFN-gamma when stimulated with concanavalin A. The kinetics of interleukin (IL)- 10 production by ConA (ConA)-stimulated spleen cell were inversely correlated with IFN-gamma levels throughout the course of acute infection in all mouse strains. Levels of IL-2 produced by ConA-stimulated spleen cells were also initially high (day 0) then decreased as acute infection progressed. Conversely, IL-4 production by ConA-stimulated spleen cells increased during infection, and mice that express the susceptible C3H background produced significantly more IL-4 than those that share the resistant B10 background. IL-2 production by lymph node cells from mice that express the susceptible C3H genetic background also declined during infection, while lymph node cells from B10 background mice showed a moderate increase in IL-2 secretion. These data suggest that both the levels and the kinetics of cytokine production may be genetically regulated and that cytokine responses are compartmentalized in the T. cruzi-infected host.