Obesity (BMI ≥30 kg/m(2)) increases the risk of developing lifestyle-related diseases. A subgroup of obese individuals has been described as "metabolically healthy, but obese" (MHO). In contrast to at-risk obese (ARO), the MHO phenotype is defined by a favourable lipid profile and a normal or only slightly affected insulin sensitivity, despite the same amount of body fat. The objective was to characterize the metabolic phenotype of MHO subjects. We screened a variety of genes involved in lipid metabolism and inflammation in peripheral blood mononuclear cells (PBMC). Obese subjects (men and women; 18-70 years) with BMI ≥30 kg/m(2) were characterized as MHO (n = 9) or as ARO (n = 10). In addition, eleven healthy, normal weight subjects characterized as healthy by the same criteria as described for the MHO subjects were included. We found that with similar weight, total fat mass and fat mass distribution, the ARO subjects have increased plasma levels of gamma-glutamyl transpeptidase and free fatty acids. This group also has altered expression levels of a number of genes linked to lipid metabolism in PBMC with reduced gene expression levels of uncoupling protein 2, hormone-sensitive lipase and peroxisome proliferator-activated receptor δ compared with MHO subjects. The present metabolic differences between subgroups of obese subjects may contribute to explain some of the underlying mechanisms causing the increased risk of disease among ARO subjects compared with MHO subjects.