ABSTRACT: BACKGROUND: Low plasma high-density lipoprotein-cholesterol (HDL-c) level is commonly present in obesity and represents an independent cardiovascular risk factor. However, obese patients are a very heterogeneous population and the factors and mechanisms that contribute to low HDL-c remain unclear. The aim of this study was to investigate the association between plasma HDL-c levels and plasma hormonal profiles (insulin, adiponectin, resistin, leptin and ghrelin) in subsets of class II and III obese patients. METHODS: Fasting plasma levels of glucose, total cholesterol, LDL-c, HDL-c, triglycerides, free fatty acids, apoproteins A-I, B-100, B-48, C-II, C-III, insulin, hs-CRP, adipocytokines (adiponectin, resistin, leptin), unacylated ghrelin, body composition (DXA) and resting energy expenditure were measured in three subsets of obese patients: 17 metabolically abnormal obese (MAO) with metabolic syndrome and the typical metabolic dyslipidaemia, 21 metabolically healthy obese (MHO) without metabolic syndrome and with a normal lipid profile, and 21 isolated low HDL-c obese patients (LHO) without metabolic syndrome, compared to 21 healthy lean control subjects. RESULTS: Insulin resistance (HOMA-IR) increased gradually from MHO to LHO and from LHO to MAO patients (p < 0.05 between MHO and MAO and between LHO and MAO). In multiple regression analysis, serum unacylated ghrelin levels were only positively and independently associated with HDL-c levels in the LHO group (p = 0.032). CONCLUSIONS: These results suggest that, in class II and III obese patients with an isolated low HDL-c phenotype, unacylated ghrelin is positively associated with HDL-c level independently of insulin resistance and CRP levels, and may contribute to the highly prevalent low HDL-c level seen in obesity.