Clusterin, a protein constituent of HDL, was recently shown to bind plasma leptin in vitro and has been proposed to modulate leptin activity. To gain insight into a possible role for plasma clusterin in human obesity, we measured plasma clusterin, leptin, soluble leptin receptor (sObR), and lipoproteins in 70 obese adolescents (12.4 Ϯ 1.6 y; BMI-SD score (SDS-BMI) 2.35 Ϯ 0.47) before and after 3 wk of weight reduction in a dietary camp and in 44 normal weight controls. Binding of plasma leptin to HDL or clusterin was studied using ultracentrifugation and immunoaffinity chromatography. During weight reduction, clusterin decreased from 14.6 Ϯ 4.1 to 10.3 Ϯ 2.9 mg/dL, p Ͻ 0.001) in obese adolescents, whereas sObR increased. However, baseline plasma clusterin in obese adolescents did not differ from controls. Clusterin did not correlate with SDS-BMI, weight loss, leptin, or lipoproteins. Only ϳ1% of plasma leptin was associated with clusterin/apoA-I complexes or with HDL. Our results do not support a role for plasma clusterin as an important leptin-binding protein or modulator of leptin action. The decrease of plasma clusterin during weight reduction may be an effect of the hypocaloric diet rather than being directly linked to weight loss. (Pediatr Res 69: 237-242, 2011)