Increased leptin levels are associated with cardiovascular disease in obesity although the mechanism is unknown. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a key regulator of macrophage lipid metabolism and its activation by thiazolidinediones protects against atherosclerosis. The aim of this study was to assess the effects of human recombinant leptin on PPARgamma mRNA levels in primary human macrophages and macrophage-derived foam cells. Leptin treatment (100 ng/ml) for 24 h caused a 41% reduction (p < 0.01) in PPARgamma transcript levels in human-derived macrophages. This fall was accompanied by a reduction in the mRNA expression of carnitine palmitoyltransferase (CPT-I) (36%, p < 0.05) and ABCA1 (62%, p < 0.05), whereas CD36 mRNA reduction (34%) was not significant. In macrophage-derived foam cells, leptin at 20 ng/ml reduced PPARgamma mRNA levels by 33% (p < 0.01) and CPT-I by 27% (p < 0.05). At this concentration, leptin did not modify the expression of either ABCA1 or CD36. In agreement with these results, intracellular cholesterol ester accumulation was not altered in macrophage-derived foam cells by leptin at 20 ng/ml. We propose that the reduction in PPARgamma expression in both macrophages and foam cells may be one of the factors linking high leptin levels and cardiovascular disease.