Th1-type immune response plays a critical role in resistance to Trypanosoma cruzi infection. We asked whether a synthetic oligodeoxynucleotide that contains immunostimulatory CpG motifs (CpG ODN), known to promote a Th1 response, could act as an adjuvant in immunization with parasite antigens. Mice immunized with a whole homogenate (WH) of T. cruzi antigens co-administered with CpG ODN presented high titers of T. cruzi antibodies (IgG2a isotype), strong delayed type hypersensitivity and a Th1-dominated (IFN-gamma and IL-12) cytokine profile. Furthermore, WH plus CpG ODN protected mice from challenge with an otherwise lethal dose of bloodstream trypomastigotes. As reported for leishmaniasis and malaria, CpG ODN holds considerable promise as an adjuvant for future vaccines against T. cruzi.