To investigate the associations of uncoupling protein (UCP)2 and UCP3 gene variants with overweight and related traits, we genotyped UCP2-866G>A, UCP2Ala55Val, and UCP3-55C>T in 737 Korean children and 732 adults and collected data regarding anthropometric status and blood biochemistry. Information concerning the children's lifestyles and dietary habits was collected. The UCP2-866G>A and UCP3-55C>T gene variants showed significant associations with BMI level, waist circumference, and body weight in the children but not in the adults. Compared with -866GG carriers, the -866GA and AA carriers showed a strong decreasing trend in the risk for overweight (odds ratio (OR), 0.67; 95% confidence interval (CI), 0.45-1.01; P = 0.053). In comparison with UCP3-55CC carriers, children carrying -55CT and TT showed a significant reduction in the risk of overweight (OR, 0.67; 95% CI, 0.46-0.98; P = 0.039). There was also evidence of interactions between the effects of the combined UCP2-UCP3 genotype and obesity-related metabolic traits. The greatest protective effect against overweight was seen in those with the combined genotype non-UCP2-866GG and non-UCP3-55CC, as compared with those carrying both UCP2-866GG and UCP3-55CC (OR,0.60; 95% CI, 0.38-0.95; P = 0.030). In the subgroup with a low level of physical activity, UCP3-55CC carriers had higher BMI values than UCP3-55T carriers (16.6 +/- 2.3 kg/m(2) vs. 16.1 +/- 1.9 kg/m(2), P = 0.016). Low physical activity may aggravate the susceptibility to overweight in UCP2-866GG and UCP3-55CC carriers.