The peroxisome proliferator-activated receptors (PPARs) are a family of fatty acid-activated transcription factors which control lipid homeostasis and cellular differentiation. PPARa (NR1C1) controls lipid oxidation and clearance in hepatocytes and PPAR? (NR1C3) promotes preadipocyte differentiation and lipogenesis. Drugs that activate PPARa are effective in lowering plasma levels of lipids and have been used in the management of hyperlipidemia. PPAR? agonists increase insulin sensitivity and are used in the management of type 2 diabetes. In contrast, there are no marketed drugs that selectively target PPARd (NR1C2) and the physiological roles of PPARd are unclear. In this report we demonstrate that the expression of PPARd is increased during the differentiation of human macrophagesin vitro. In addition, a highly selective agonist of PPARd (compound F) promotes lipid accumulation in primary human macrophages and in macrophages derived from the human monocytic cell line, THP-1. Compound F increases the expression of genes involved in lipid uptake and storage such as the class A and B scavenger receptors (SRA, CD36) and adipophilin. PPARd activation also represses key genes involved in lipid metabolism and efflux, i.e.cholesterol 27-hydroxylase and apolipoprotein E. We have generated THP-1 sublines that overexpress PPARd and have confirmed that PPARd is a powerful promoter of macrophage lipid accumulation. These data suggest that PPARd may play a role in the pathology of diseases associated with lipid-filled macrophages, such as atherosclerosis, arthritis, and neurodegeneration.