['We examined whether or not the association of physical activity with type 2 diabetes incidence differs according to several types of genetic susceptibility.', 'In a large prospective cohort with 821 incident cases of type 2 diabetes, we examined interactions of physical activity with: (1) each of 65 type 2 diabetes-associated single nucleotide polymorphisms (SNPs); (2) a genetic risk score (GRS) comprising all 65 SNPs; (3) two GRSs comprised of SNPs implicated in insulin resistance (IR) and insulin secretion; (4) GRSs for fasting insulin (FI) and fasting glucose.', 'We found a significant interaction of physical activity and the type 2 diabetes GRS (p interaction\u2009=\u20090.016), suggesting a weaker protective effect of physical activity in those at high genetic risk. Based on the interactions observed with the IR GRS (p interaction\u2009=\u20090.046) and the FI GRS (p interaction\u2009=\u20090.042), it appears that the overall type 2 diabetes GRS interaction most likely occurs through genetic susceptibility to IR as opposed to insulin secretion. Furthermore, this interaction was more pronounced in women (p interaction\u2009=\u20090.0025) than in men (p interaction\u2009=\u20090.46). No single SNP stood out as displaying a strong interaction with physical activity.'] Is association of physical activity with lower type 2 diabetes incidence weaker among individuals at high genetic risk?