The G1057D polymorphism in the insulin receptor substrate-2 (IRS-2) gene has been reported to be associated with insulin resistance, obesity and type 2 diabetes. However little is known about its possible association with cancer. To investigate this association, we determined the distribution of its genotypes and frequency of alleles in endometrial cancer patients.The study population consisted of 184 subjects: 44 patients with endometrial cancer and 140 controls without cancer. All the patients were primarily treated with surgical intervention. DNA was extracted from the leucocytes by high pure polymerase chain reaction (PCR) template preparation kit. Genetic polymorphism of IRS-2 G1057D was detected by using PCR-based restriction fragment-length polymorphism.For IRS-2 G1057D polymorphism, there was a significant difference in genotype distribution and allele frequency between endometrial cancer patients and controls (p < 0.001). The risk for endometrial cancer was 4.87 times higher in the individuals with the IRS-2 DD genotype compared to the GG genotype [95% confidence interval (CI): 1.74-13.63 p = 0.003]. Also individuals with the IRS-2 D allele had a significantly higher risk of endometrium cancer compared with individuals with the IRS-2 G allele, with a relative risk of 2.23 (95% CI: 1.36-3.67, p = 0.001) for cases compared with population controls.These results suggest that IRS-2 G1057D polymorphism may be associated with endometrial cancer.