We have previously shown that murine interferon gamma (IFNγ) and its C-terminal peptide, muIFNγ(95-133), bind to a region on the cytoplasmic domain of the IFNγ receptor contained in the synthetic peptide, MIR(253-287). This region of the murine receptor bears considerable homology (≍ 80%) to its human counterpart. Here we report that not only do human IFNγ and the human IFNγ C-terminal peptide, huIFNγ(95-134), bind to the cytoplasmic domain of the human IFNγ receptor, but also that this interaction is species non-specific. MuIFNγ(95-133) binds to human IFNγ receptor cytoplasmic peptide HIR(252-291), and huIFNγ(95-134) binds to MIR(253-287). Furthermore, treatment of murine macrophage cell lines with C-terminal peptides of either murine or human IFNγ results in 10-fold upregulation of MHC class II molecule expression and increased resistance to infection with vesicular stomatitis virus (VSV) (10⁶ - 10⁹-fold reduction in yield). These data suggest a direct role for the C-terminus of IFNγ in the initiation of intracellular signalling processes and may be indicative of a more general mechanism of action for extracellular signalling molecules.