By combining data from 218,166 adults from 45 studies, we confirm that PA attenuates the influence of FTO variation on BMI and obesity. The association of the FTO rs9939609 variant with BMI and with the odds of obesity was reduced by approximately 30% in physically active compared to inactive adults. We also found an interaction effect on the odds of overweight and on waist circumference and body fat percentage. No interaction between FTO and PA was found in our meta-analysis of 19,268 children and adolescents.