A diverse spectrum of unique peptide-MHC class I complexes guides CD8 T cell responses toward viral or stress-induced Ags. Multiple components are required to process Ag and facilitate peptide loading in the endoplasmic reticulum. IFN-γ, a potent proinflammatory cytokine, markedly up-regulates transcription of genes involved in MHC class I assembly. Physiological mechanisms which counteract this response are poorly defined. We demonstrate that promoters of functionally linked genes on this pathway contain conserved regulatory elements that allow antagonistic regulation by IFN-γ and the transcription factor B lymphocyte-induced maturation protein-1 (also known as PR domain-containing 1, with ZNF domain (PRDM1)). Repression of ERAP1, TAPASIN, MECL1, and LMP7 by PRDM1 results in failure to up-regulate surface MHC class I in response to IFN-γ in human cell lines. Using the sea urchin prdm1 ortholog, we demonstrate that the capacity of PRDM1 to repress the IFN response of such promoters is evolutionarily ancient and that dependence on the precise IFN regulatory factor element sequence is highly conserved. This indicates that the functional interaction between PRDM1 and IFN-regulated pathways antedates the evolution of the adaptive immune system and the MHC, and identifies a unique role for PRDM1 as a key regulator of Ag presentation by MHC class I.