The insulin receptor substrate-1 (IRS-1) gene has been considered a candidate for insulin resistance, type 2 diabetes, and coronary artery disease. To investigate the relationship between the common Gly(972)Arg IRS-1 variant and the presence of cardiovascular risk factors, 153 glucose-tolerant, unrelated offspring of type 2 diabetic patients were studied. There were no differences between Arg(972) IRS-1 carriers and noncarriers in age, gender, body mass index, waist/hip ratio, body composition, fasting glucose and insulin levels, and glucose or insulin levels during the oral glucose tolerance test. Insulin sensitivity, assessed by hyperinsulinemic-euglycemic clamp, was significantly reduced in carriers of Arg(972) IRS-1 (P < 0.03). Carriers of Arg(972) IRS-1 displayed many features of the insulin resistance syndrome, including higher values for serum triglycerides (P < 0.01), total/high density lipoprotein cholesterol ratio (P < 0.01), free fatty acid levels (P < 0.04), systolic blood pressure (P < 0.04), microalbuminuria (P < 0.003), and intima-media thickness (P < 0.02). These results suggest that the Arg(972) IRS-1 variant could contribute to the risk for atherosclerotic cardiovascular diseases associated with type 2 diabetes by producing a cluster of insulin resistance-related metabolic abnormalities.