BACKGROUND: The development of obesity is still a poorly understood process that is dependent on both genetic and environmental factors. OBJECTIVE: The objective was to examine how physical activity and the proportion of energy as protein in the diet modify the genetic variation of body mass index (BMI), waist circumference, and percentage body fat. DESIGN: Twins from Denmark (756 complete pairs) and Finland (278 complete pairs) aged 18-67 and 21-24 y, respectively, participated. The proportion of energy as protein in the diet was estimated by using food-frequency questionnaires. The participants reported the frequency and intensity of their leisure time physical activity. Waist circumference and BMI were measured. Percentage body fat was assessed in Denmark by using a bioelectrical impedance method. The data were analyzed by using gene-environment interaction models for twin data with the Mx statistical package (Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA). RESULTS: High physical activity was associated with lower mean values, and a high proportion of protein in the diet was associated with higher mean BMI, waist circumference, and percentage body fat and a reduction in genetic and environmental variances. Genetic modification by physical activity was statistically significant for BMI (-0.18; 95% CI: -0.31, -0.05) and waist circumference (-0.14; 95% CI: -0.22, -0.05) in the merged data. A high proportion of protein in the diet reduced genetic and environmental variances in BMI and waist circumference in Danish men but not in women or in Finnish men. CONCLUSIONS: Our results suggest that, in physically active individuals, the genetic variation in weight is reduced, which possibly suggests that physical activity is able to modify the action of the genes responsible for predisposition to obesity, whereas the protein content of the diet has no appreciable effect.