The relationship between the Gly972Arg polymorphism in the insulin receptor substrate-1 (IRS-1) gene and metabolic risk markers is not clear, possibly due to small sample sizes. Modification by body mass index (BMI) has also been suggested. Our aim was therefore to quantify the association of this 972Arg-variant with insulin, glucose and lipid levels in overweight and non-overweight subjects with oversampling of subjects with the 972Arg-variant. We first genotyped 3684 subjects selected from a large population-based cohort (n approximately 23000) according to BMI (26-40 or 18-24 kg/m(2)). Next, we examined 600 of these subjects for fasting metabolic risk markers according to BMI-group and genotype. Subjects with the 972Arg-variant had significantly higher insulin concentrations (4.09 pmol/l or 9.6%, P=0.024) and lower triglyceride levels (0.13 mmol/l or 11%, P=0.001) compared with non-carriers when adjusted for age, sex, waist-to-hip ratio, BMI, alcohol consumption, physical activity and cigarette smoking. These associations were more pronounced in the high BMI-group, although the interactions were not statistically significant. Our large population-based sample shows that the IRS-1 Gly972Arg polymorphism relates to higher fasting insulin levels and lower triglyceride levels. The impact of this genotype and its modification by overweight may be smaller than suggested previously.