Considerable progress has been made recently in the discovery of the genetic basis of T2D and related metabolic traits [7], which now enables formal investigation of the interaction between genes and lifestyle in the risk of developing T2D. The Diabetes Prevention Program (DPP) study detected no significant interactions between treatment groups and genetic risk assessed on the basis of 34 T2D loci established at the time [8]. However, this study included only high-risk individuals and may have been underpowered because of the small number of people in each sub-group (947 in the placebo group, 955 in the lifestyle intervention group, and the 941 metformin group), even in this relatively large intervention trial. A complementary approach to the analysis of lifestyle trials is the investigation of interactions between genetic and lifestyle factors in observational cohort studies. However, such interactions have not been systematically investigated in prospective cohorts with standardised assessment of lifestyle factors at baseline and adequate statistical power. We therefore sought to investigate this question in a large case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study.