<i>Background/Aims:</i> Genome-wide association studies have led to the identification of several susceptibility genes for type 2 diabetes mellitus (T2DM). The objective of this study was to test the hypothesis that the associations between single nucleotide polymorphisms (SNPs) in these genes and adiposity and glucose homeostasis-related phenotypes are influenced by dietary fat intake. <i>Methods:</i> Thirty-three SNPs in 9 T2DM genes <i>(CDKAL1, CDKN2A/B, HHEX, HNF1B, IGF2BP2, KCNJ11, SLC30A8, TCF7L2</i> and <i>WFS1)</i> were tested in a maximum of 669 subjects from the Quebec Family Study. Subjects were measured for several adiposity indices and underwent a 75-gram oral glucose tolerance test. Total fat intake was estimated from a 3-day dietary record. <i>Results:</i> We observed 13 significant (p ≤ 0.01) SNP-dietary fat interactions. Among them, <i>IGF2BP2</i> rs4402960, alone or in interaction with dietary fat intake, influenced abdominal total fat (ATF: SNP effect, p = 0.006, interaction effect, p = 0.009) and abdominal visceral fat (AVF: SNP effect, p = 0.007, interaction effect, p = 0.01). Similarly, <i>TCF7L2</i> rs12573128 alone or in interaction with dietary fat intake, influenced insulin sensitivity (SNP effect and interaction effect, p ≤ 0.008) and glucose tolerance (SNP effect p ≤ 0.009 and interaction effect, p ≤ 0.01). <i>Conclusion:</i> These results suggest that gene-dietary fat interactions may influence glucose homeostasis-related phenotypes and play an important role in determining the increased risk of diabetes associated with the T2DM susceptibility genes.