Early interactions between the protozoan parasite Trypanosoma cruzi and mammalian hosts at primary sites of infection (skin and mucosal membranes) are predicted to be critical determinants of parasite survival and dissemination in the host. To investigate the early host response triggered by three different strains of T. cruzi at a local infection site, changes in host gene expression were monitored in a murine intradermal infection model using Affymetrix oligonucleotide arrays. Robust induction of IFN-stimulated genes was observed in excised skin 24 h postinfection where the level of IFN-stimulated gene induction was parasite strain-dependent, with the least virulent strain triggering a muted IFN response. Infection of mice immunodepleted of IFN-gamma-producing cells or infection of IFN-gamma-deficient mice had minimal impact on the IFN response generated in T. cruzi-infected mice. In contrast, infection of mice lacking the type I IFN receptor demonstrated that type I IFNs are largely responsible for the IFN response generated at the site of infection. These data highlight type I IFNs as important components of the innate immune response to T. cruzi at the site of inoculation and their role in shaping the early transcriptional response to this pathogen.