Niacin, the first lipid lowering drug shown to improve survival after myocardial infarction, decreases LDL and increases HDL cholesterol levels. These effects cannot fully be explained by its suspected mechanism of action, inhibition of lipolysis and hepatic VLDL synthesis. Niacin has also been shown to interfere with the cyclic AMP (cAMP)/protein kinase A (PKA) pathway and massively stimulate prostaglandin D₂ (PGD₂) formation. The major metabolite of PGD₂, 15-deoxy-Δ^12,14-prostaglandin J₂ (15d-PGJ₂), was recently identified as the most potent endogenous PPARγ activator. We, therefore, studied the effects of niacin on the PPARγ- and cAMP-dependent expression of receptors promoting reverse cholesterol transport. The transcription of PPARγ-, HDL-, LDL- and scavenger-receptors and the sterol exporter ABCA1, were measured by quantitative RT-PCR and cellular cholesterol efflux and PPARγ activation studied in macrophage and hepatocyte models. Niacin stimulated the translocation of PPARγ and the transcription of PPARγ, CD36 and ABCA1 in monocytoid cells, whereas the LDL-receptor (LDL-R) was unchanged. Thereby niacin enhanced HDL-mediated cholesterol efflux from the cells resulting in a reduced cellular cholesterol content. The niacin effect on CD36 but not on ABCA1 was prevented by cyclooxygenase inhibition, whereas the niacin effect on ABCA1 but not on CD36 was prevented by PKA inhibition, suggesting mediation by the 15d-PGJ₂/PPARγ and the cAMP/PKA pathways, respectively. These new actions of niacin on several key effectors of reverse cholesterol transport out of the vessel wall provide a rational to expect regression of atherosclerosis and test the combination of niacin with statins for an overadditive clinical benefit.