Clustering of risk factors for cardiovascular disease related to insulin resistance may account for the increased incidence of vascular disease in these conditions and in non-diabetic subjects. To investigate the relationship between a coding polymorphism in the insulin receptor substrate-1 gene and the presence of cardiovascular risk factors, 209 patients with NIDDM and 452 subjects investigated for coronary artery disease (CAD) were studied. In the NIDDM subjects 22 (10.5%) were heterozygous at codon 972 for a polymorphism which codes for a glycine to arginine substitution and 187 (89.5%) were homozygous for the wild type. Patients with the mutation had lower levels of cholesterol compared with wild type (mean, 95% confidence intervals), 5.3 (4.9-5.8) vs 6.0 (5.9-6.2) mmol/l, respectively (P = 0.002), triglyceride 1.7 (1.4-2.1) vs 2.2 (2.0-2.4) mmol/l (P = 0.051), factor VII:C activity 109.5 (85.5-133.5) vs 133.5 (127-140)% (P = 0.057) and PAI-1 antigen, 16.0 (10.5-24.3) vs 22.2 (20.0-24.6) ng/ml (P = 0.054). There were no differences in body mass index, indices of glycaemic control, fasting insulin or the prevalence of hypertension. In patients with CAD, 55 (12.7%) were carriers of the mutation (including three homozygotes) (NIDDM vs CAD, NS). Although similar trends in cholesterol, factor VII, PAI-1 antigen and triglyceride existed between carriers of the mutation and the wild type, none reached statistical significance. The results indicate that the IRS-1 gene is not implicated in the pathogenesis of NIDDM or CAD.