The low-grade systemic inflammation seen in obesity may affect the actions of some adipose tissue-derived adipokines that are involved in the regulation of vascular function. We sought to verify whether hyperleptinemia may influence the inflammatory and atherogenic responses in obese adolescents undergoing interdisciplinary therapy. Thirty-four obese adolescents underwent interdisciplinary therapy for 1 year. Subjects were considered hyperleptinemic if they had baseline values of leptin above 20 ng/mL for boys and 24 ng/mL for girls. Both groups showed an improvement in body composition and a reduction in carotid intima-media thickness. However, only subjects in the non-hyperleptinemic group showed an increase in adiponectin concentration after therapy. Moreover, leptin concentration was positively correlated with adiponectin and inversely correlated with PAI-1 in this group. Hyperleptinemic state may impair the attenuation of inflammation in obese adolescents undergoing interdisciplinary therapy, particularly by impeding the increase in adiponectin concentration, which is directly involved in vascular protection.