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 gamma (PPARgamma), a transcription factor in the nuclear receptor superfamily, regulates gene expression in response to various activators, including 15-deoxy-delta12,14-prostaglandin J2 and the antidiabetic agent troglitazone. The role of PPARgamma in human atherosclerosis is unexplored. We report here that monocytes/macrophages in human atherosclerotic lesions (n = 12) express immunostainable PPARgamma. Normal artery specimens (n = 6) reveal minimal immunoreactive PPARgamma. Human monocytes and monocyte-derived macrophages cultured for 6 days in 5% human serum expressed PPARgamma mRNA and protein by reverse transcription-polymerase chain reaction and Western blotting, respectively. In addition, PPARgamma mRNA expression in U937 cells increased during phorbol 12-myristate 13 acetate-induced differentiation. Stimulation of PPARgamma with troglitazone or 15-deoxy-delta12,14-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, PPARgamma is present in macrophages in human atherosclerotic lesions and may regulate expression and activity of MMP-9, an enzyme implicated in plaque rupture. PPARgamma is likely to be an important regulator of monocyte/macrophage function with relevance for human atherosclerotic disease.