The present study was intended to examine whether ponderal index (PI) at birth modifies the effect of the fat mass and obesity associated (FTO) rs9939609 polymorphism on adiposity in European adolescents. A total of 628 adolescents aged 14.4 (SE 1-3) years (56-8% female) were recruited. PI was calculated from parental reports of birth weight and length (kg/m(3)), and the BMI (kg/m(2)), body fat percentage and fat mass index (FMI, kg/m(2)) were calculated. The rs9939609 polymorphism was genotyped and physical activity assessed by accelerometry. Sex, duration of pregnancy, pubertal status, centre and physical activity were used as confounders in all the analyses. The minor A allele of the FTO rs9939609 was significantly associated with higher BMI, body fat percentage and FMI (all P<0.05) but not with PI. Significant interactions between PI and the rs9939609 polymorphism in terms of body fat percentage (P=0-002) and FMI (P=0.017) were detected. However, this polymorphism was only significantly associated with higher BMI, body fat percentage and FMI (all P<005) in adolescents in the lower PI tertile. Indeed, both body fat percentage and FMI were higher in those adolescents in the lower PI tertile carrying the A allele of the FTO rs9939609 polymorphism than in those with the IT genotype (25-0 (SE 0.8) v. 22.1 (SE 1.0)%, adjusted P=0.030 and 5.6 (SE 0.3) v. 4-6 (SE 0.4) kg/m(2), P=0.031, respectively). Our findings suggest that those adolescents born with lower PI could be more vulnerable to the influence of the A risk allele of the FTO polymorphism on total adiposity content.