CD4⁺ and CD8⁺ T cells exhibit important differences in their major effector functions. CD8⁺ T cells provide protection against pathogens through cytolytic activity, whereas CD4⁺ T cells exert important regulatory activity through production of cytokines. However, both lineages can produce interferon (IFN)-γ, which can contribute to protective immunity. Here we show that CD4⁺ and CD8⁺ T cells differ in their regulation of IFN-γ production. Both lineages require signal transducer and activator of transcription (Stat)4 activation for IFN-γ induced by interleukin (IL)-12/IL-18 signaling, but only CD4⁺ T cells require Stat4 for IFN-γ induction via the TCR pathway. In response to antigen, CD8⁺ T cells can produce IFN-γ independently of IL-12, whereas CD4⁺ T cells require IL-12 and Stat4 activation. Thus, there is a lineage-specific requirement for Stat4 activation in antigen-induced IFN-γ production based on differences in TCR signaling between CD4⁺ and CD8⁺ T cells.