Multiple genetic and environmental factors underlie the etiology of type 2 diabetes. To evaluate the influence of the relationship between dietary fat intake and single nucleotide polymorphisms (SNPs) in genes involved in fat assimilation on disease susceptibility, a 2-step approach using an exploratory case-control study (n = 192/384) and an independent, confirmatory case-cohort study (n = 614/2248) taken from the same prospective study population (European Prospective Investigation into Cancer and Nutrition-Potsdam) was used. Sixty-three SNPs in 32 genes were initially analyzed. Total intake of fat and fatty acid intake were calculated from validated baseline FFQ. The SNP × nutrient interaction was tested in multivariate adjusted regression models. The initial screening step revealed evidence that, for 4 SNPs (CAV2 rs2270188, DBI rs2084202, PPARG rs1801282, and SREBF1 rs2297508), disease susceptibility might depend on the amount and quality of fat intake. The insulin receptor regulator CAV2 rs2270188 G > T SNP was found to interact with dietary fat in the confirmatory case-cohort study. Using pooled data, homozygous individuals of the rare T-allele showed a 100% greater risk of type 2 diabetes if daily fat intake was increased from 30 to 40 % energy. An increase in dietary SFA from 10 to 20 % energy predicted an ~200% greater risk of type 2 diabetes. We found preliminary evidence that CAV2 rs2270188 interacts with dietary fat to affect risk of type 2 diabetes.