A commonly occurring nucleotide polymorphism of the insulin-receptor substrate 2 (IRS-2) gene at amino acid 1057 from Glycine to Asparaginic acid (G1057D) was recently shown to be a determinant of insulin sensitivity in both glucose-tolerant individuals and those with type 2 diabetes. With respect to the latter, the IRS-2 D1057 allele increase the risk of insulin resistance among obese individuals. After we reconstructed haplotypes from the G1057D variant and the -769C/T replacement that was newly identified, we investigated the possibility that the IRS-2 gene affects insulin sensitivity in Japanese glucose-tolerant subjects (n = 260) and type 2 diabetic patients (n = 123). We did not find that the D1057 allele and haplotype pairs were associated with the risk of diabetes. However, type 2 diabetic patients, particularly obese patients, carrying the D1057 allele and the CA haplotype were associated with insulin resistance. Furthermore, we suggested that the TG and CG haplotypes might have a protective role against insulin resistance. This observation raises the possibility that both the IRS-2 D1057 allele and the CA haplotype are useful genetic markers for identifying obese individuals who are particularly susceptible to insulin resistance.