Dysfunction of high-density lipoprotein (HDL) particles that even become proinflammatory or lose atheroprotective properties is known through analyses of HDL isolated from diabetic subjects. Recently, high concentrations of HDL or apolipoprotein (apo) A-I in individuals with diabetes or coronary heart disease were found to reveal dysfunction in some population-based studies. Such dysfunction of HDL and its apos A-I, A-II, and C-III has been observed in a general population for the first time among Turkish adults. Functional defectiveness manifested itself by unexpected correlations with inflammatory biomarkers and, in long-term follow-up, by lack of protection against diabetes and coronary heart disease, accounting for the excess incidences in Turks. Female sex was more pronouncedly affected by this process that presumably exists in other ethnicities in South Asia, East Europe, and the Middle East. In contradistinction, in Western and East Asian population, only individuals with glucose intolerance or those at risk for cardiometabolic disease are considered to be or were documented in a review of clinical trials to have been affected by impaired function of HDL. High-density lipoprotein dysfunctionality is closely linked to obesity and low-grade inflammation yet seems to act partly independently of them. Cigarette smoking in overweight women with low-grade inflammation appears to offer limited protection against cardiometabolic risk. The great impact in public health of the dysfunction of protective serum proteins requires individual clinical recognition, appropriate preventive measures, and delineation of management, including with anti-inflammatory drugs. (C) 2011 Elsevier Inc. All rights reserved.