Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors expressed in a wide variety of cells. Our studies and others have demonstrated that both human and murine T cells express PPARγ and that expression can be augmented over time in mitogen-activated splenocytes. PPARγ ligands decrease proliferation and IL-2 production, and induce apoptosis in both B and T cells. PPARγ ligands have also been shown to be anti-inflammatory in multiple models of inflammatory disease. In the following study, we demonstrate for the first time that PPARγ is expressed in both murine CD4 and CD8 cells and that PPARγ ligands directly decrease IFN-γ expression by murine and transformed T cell lines. Unexpectedly, GW9662, a PPARγ antagonist, increases lymphocyte IFN-γ expression. Transient transfection studies reveal that PPARγ ligands, in a PPARγ-dependent manner, potently repress an IFN-γ promoter construct. Repression localizes to the distal conserved sequence of the IFN-γ promoter. Our studies also demonstrate that PPARγ acts on the IFN-γ promoter by interfering with c-Jun activation. These studies suggest that many of the observed anti-inflammatory effects of PPARγ ligands may be related to direct inhibition of IFN-γ by PPARγ.