The action of type I IFN (IFN-I) on APCs is well studied, but their direct effect on CD4 T cells is unclear. To address this, we transferred IFN-I receptor-deficient (IFN-IR 0) and-sufficient (wild-type, WT) TCR-transgenic CD4 T cells into WT mice and analyzed their response to immunization. In response to lymphocytic choriomeningitis virus immunization, WT CD4 T cells expanded∼ 100-fold, whereas IFN-IR 0 CD4 T cells expanded< 10-fold. However, both WT and IFN-IR 0 CD4 T cells expanded∼ 10-fold after Listeria monocytogenes immunization. Poor expansion of IFN-IR 0 CD4 T cells after lymphocytic choriomeningitis virus immunization was not due to a defect in proliferation or initial activation but to poor survival of the daughter cells. Thus, direct IFN-I signals can play either a critical or minimal role in CD4 T cell clonal expansion depending on the specific pathogen.