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We conducted a gene-environment interaction study to evaluate whether the association of body mass index (BMI) associated meta genome-wide association study single-nucleotide polymorphisms (SNPs) (as a genetic risk score) and BMI is modified by physical activity and age.In 8,206 women of European ancestry from the Women's Health Initiative (WHI), we used linear regression to examine main effects of the 95 SNP BMI genetic risk score (GRS) and physical activity on BMI, and evaluated whether genetic associations are modified by physical activity (two-way interaction) and age (three-way interaction).We found evidence for modification of the BMI GRS-BMI association according to both physical activity and age. We observed a significant two-way interaction of BMI GRS × physical activity in the crude model (P interaction = 0.05), where a smaller effect of the BMI GRS on BMI with increasing physical activity. The beta coefficient was 0.05 (standard error [SE] = 0.02, P = 0.01) for the high-activity group compared with beta = 0.13 (SE = 0.02, P = 4.8 × 10−9) for the sedentary group. The three-way interaction was statistically significant (adjusted P interaction = 0.01). Notably, in the 70+ age group, the BMI GRS-BMI association was attenuated and no longer significant in the high-activity group; the beta coefficient for the 70+ high-activity group was relatively small and nonsignificant (beta = 0.02, SE = 0.03, P = 0.58) compared with 70+ sedentary group (beta = 0.17, SE = 0.03, P = 2.5 × 10−7).Our study suggests that physical activity attenuates the influence of genetic predisposition to obesity, and this effect is more profound in the oldest age group.