MyD88 is the main adaptor molecule for TLR and IL-1R family members. Here, we demonstrated that T-cell intrinsic MyD88 signaling is required for proliferation, protection from apoptosis and expression of activation/memory genes during infection with the intracellular parasite Trypanosoma cruzi , as evidenced by transcriptome and cytometry analyses in mixed bone-marrow (BM) chimeras. The lack of direct IL-18R signaling in T cells, but not of IL-1R, phenocopied the absence of the MyD88 pathway, indicating that IL-18R is a critical MyD88-upstream pathway involved in the establishment of the Th1 response against an in vivo infection, a presently controvert subject. Accordingly, Il18r1 ^-/- mice display lower levels of Th1 cells and are highly susceptible to infection, but can be rescued from mortality by the adoptive transfer of WT CD4 ⁺ T cells. Our findings establish the T-cell intrinsic IL-18R/MyD88 pathway as a crucial element for induction of cognate Th1 responses against an important human pathogen.