We examined the association between the FTO rs9939609 polymorphism and serum leptin concentrations in adolescents. The FTO rs9939609 polymorphism was genotyped, and fasting serum leptin and insulin were measured in 655 European adolescents (365 females) aged 14.6 ± 1.2 years. We measured weight, height, triceps and subscapular skinfolds and waist circumference, and body fat percentage was calculated. Sex, pubertal status, center, physical activity (accelerometry), total or central adiposity and serum insulin concentrations were entered as confounders in the analyses. The minor A allele of the FTO rs9939609 was significantly associated with higher serum leptin concentrations independently of potential confounders including adiposity (+3.9 ng ml(-1) per risk allele (95% confidence interval: 2.0, 5.9); adjusted P < 0.001). These findings could link the FTO gene with serum leptin and consequently with the control of energy balance. Leptin could be a possible intermediary contributing to the association between the FTO rs9939609 polymorphism and adiposity.