Insulin receptor substrate 2 (IRS2) plays a crucial role in the regulation of insulin signaling. Several polymorphisms of the gene encoding IRS2 have been identified. The variant causing Gly1057Asp substitution is relatively frequent in humans and its impact on insulin sensitivity seems to be dependent on age and body weight. The aim of our study was to evaluate the relationships between Gly1057Asp variant and insulin sensitivity assessed by HOMA, and adiposity evaluated by measurement of epicardial fat (EpiF) thickness in the elderly. We studied 87 subjects, 42 men and 45 women, mean age±SD: 74.23±7.24years. In the subjects carrying the Gly1057Asp variant of the IRS2 gene we found higher HOMA index values (3.40±1.14 vs. 2.21±1.25, p<0.001) and increased epicardial adipose tissue (11.77±1.65 vs. 10.43±1.93mm, p<0.001) compared to wild type subjects. Univariate linear regression analyses evidenced that HOMA index was correlated with BMI (beta=0.152, p<0.001), fasting plasma glucose (beta=0.018, p=0.002), LDL cholesterol (beta=0.008, p=0.024), total cholesterol (beta=0.007, p=0.039), weight (beta=0.054, p<0.001), presence of Gly1057Asp variant (beta=1.185, p<0.001) and EpiF thickness (beta=0.540, p<0.001). In multivariate analysis HOMA index was still associated with the presence of the Gly1057Asp variant of the IRS-2 gene (beta=0.568, p=0.002) and with EpiF thickness (beta=0.414, p<0.001). Furthermore, a statistically significant positive correlation between EpiF thickness and HOMA was found (r=0.773, p<0.001) and this was not different between wild type control subjects and carriers of Gly1057Asp variant of the IRS2 gene (p=0.718). Similar results were obtained in comparing subjects with normal fasting glucose levels. In conclusion, in our elderly subjects the presence of the allelic variant Gly1057Asp of IRS2 gene was associated to the degree of insulin resistance assessed by HOMA index and with EpiF thickness, independently from the extent of obesity, suggesting its contribution to global cardiometabolic risk.