The aim of this study was to evaluate the effect of a six-month lifestyle intervention on adiponectin, resistin, and two soluble forms of tumor necrosis factor-α receptor (sTNFR) in obese adolescents. A total of 54 obese adolescents aged 10 to 16 years completed the program. Twenty-four adolescents with normal weight at baseline were used as a control group. Our results demonstrated that obese adolescents had abnormal lipid profile, homeostasis model assessment (HOMA) index, adiponectin level (5.6 ± 2.7 vs. 7.6 ± 2.9 μg/mL, p = 0.005) as well as resistin level (31.0 ± 9.0 vs. 24.3 ± 8.5 ng/mL, p = 0.003), whereas levels of both sTNFRs were similar to those in normal weight subjects. After the six-month lifestyle intervention, obese adolescents had a slight but significant drop in standard deviation score-body mass index (SDS-BMI), a significant decrease in waist circumference, total cholesterol, triglycerides, HOMA index, as well as resistin, and a significant increase in adiponectin and high-density lipoprotein-cholesterol. In adolescents without decreased SDS-BMI, no change was observed in adipokines. Changes in adiponectin correlated negatively with changes in waist circumference (r = -0.275, p = 0.044). Changes in resistin correlated positively with changes in triglycerides (r = 0.302, p = 0.027). The study demonstrated the increase of resistin and the decrease of adiponectin in obese adolescents. Lifestyle intervention improved adipokine abnormalities in obese subjects.