Mononuclear phagocytes play an important role in atherosclerosis and its sequela plaque rupture in part by their secretion of matrix metalloproteinases (MMPs), including MMP-9. Peroxisomal proliferator-activated receptor γ (PPARγ), a transcription factor in the nuclear receptor superfamily, regulates gene expression in response to various activators, including 15-deoxy-Δ^12,14-prostaglandin J₂ and the antidiabetic agent troglitazone. The role of PPARγ in human atherosclerosis is unexplored. We report here that monocytes/macrophages in human atherosclerotic lesions (n = 12) express immunostainable PPARγ. Normal artery specimens (n = 6) reveal minimal immunoreactive PPARγ. Human monocytes and monocyte-derived macrophages cultured for 6 days in 5% human serum expressed PPARγ mRNA and protein by reverse transcription-polymerase chain reaction and Western blotting, respectively. In addition, PPARγ mRNA expression in U937 cells increased during phorbol 12-myristate 13 acetate-induced differentiation. Stimulation of PPARγ with troglitazone or 15-deoxy-Δ^12,14-prostaglandin J₂ in human monocyte-derived macrophages inhibited MMP-9 gelatinolytic activity in a concentration-dependent fashion as revealed by zymography. This inhibition correlates with decreased MMP-9 secretion as determined by Western blotting. Thus, PPARγ is present in macrophages in human atherosclerotic lesions and may regulate expression and activity of MMP-9, an enzyme implicated in plaque rupture. PPARγ is likely to be an important regulator of monocyte/macrophage function with relevance for human atherosclerotic disease.