Werner's syndrome is characterized by premature aging and frequent impaired glucose tolerance or overt diabetes. Insulin resistance may play an important role and may be caused by a post-receptor defect or dysfunctional insulin receptor. The present study was undertaken to investigate the insulin receptor gene mutation in Werner's syndrome. The genomic DNAs were obtained from four patients with Werner's syndrome. Exons 2-22 of the insulin receptor gene except exon 1 were amplified from genomic DNA by the polymerase chain reaction and screened for nucleotide variation by examining for single-stranded conformational polymorphisms. There were no nucleotide variations in exons 2, 4-->7, 9 and 12-->22. Variants were thus found in exons 3, 8, 10 and 11 and each were sequenced. The variant in exon 8 was due to a silent polymorphism (GAT-->GAC/T, Asp519) and other variants in exons 3, 10 and 11 were caused by nucleotide substitutions in introns. These results suggest that the patients with Werner's syndrome express normal insulin receptors and that the primary genetic lesion for insulin resistance is not in the insulin receptor gene. Insulin resistance in Werner's syndrome is thus likely by a post-receptor defect.