Obesity is a leading risk factor for type 2 diabetes and cardiovascular disease. Recent data suggest that one in three children in the UK is overweight or obese, and the prevalence is increasing. The discovery of the FaT mass and Obesity associated (FTO) gene has provided compelling evidence of genetic variation in the general population that influences fat levels and risk of obesity (1). Individuals carrying certain variants of this gene are at increased risk of obesity and have greater measures of fatness than non-carriers. The interaction of genetic and environmental factors requires investigation to understand how environment can modulate genetic contributions to risk of obesity. 949 11-18 year old Greek adolescents from the EUREKA study (Males: N=499; Females: N=450) were genotyped at the FTO rs17817449 polymorphism, and their weight, BMI, triceps and subscapular skinfolds were measured. Those reporting more than the compulsory 2hrs of school-based physical activity by questionnaire were classified as active, while others were classified as inactive. Age and gender sub-groups were transformed and z-scores applied in each sub-group. Data are presented reverse-transformed based on 17-18 year old male values. The population was in Hardy-Weinberg Equilibrium. ANOVA analysis in all subjects showed an effect of FTO genotype on weight (P=0.017), with a T-dominant model explaining 99% of the genetic variance. All subsequent analyses were performed using this model and showed that FTO genotype influenced weight (P=0.005), BMI (P=0.012), triceps (P=0.02) and subscapular skinfolds (P=0.028). Homozygotes for the G-allele (GGs) had a 3kg increase in weight relative to T-carriers, and higher BMI and skinfolds. Gender sub-group analysis revealed effects on weight (P=0.01) and BMI (P=0.027) in males but not females. GLM-ANOVA analysis of weight in males revealed an interaction between physical activity and FTO genotype (P=0.01). The influence of FTO genotype was more pronounced in inactive males, and effects were found on weight (P=0.001), BMI (P=0.002), triceps (P=0.013) and subscapular skinfolds (P = 0.045). Inactive GG carriers displayed the equivalent of an almost 10kg increase in weight ((Data are mean (95% C.I) GG = 80.9kg (75.29-86.95), T-carriers = 70.99kg (68.3-73.78)), and 3 BMI units (GG = 25.68 (24.24-27.31), T-carriers = 22.92 (22.17-23.72)). Post-hoc analyses revealed that inactive GGs had higher adiposity than active GGs and all T-carriers; but that physically active GGs did not differ from T-carriers in any phenotypic measurement. It is concluded that FTO genotype at rs17817449 influences variation in obesity-related measures, and that GG individuals display higher levels of adiposity than T-carriers. However, a key finding of this study is that physically active carriers of the “fat variant” display the same levels of adiposity as non-carriers.