Continuous infusion of glucose with model assessment was used to measure glucose tolerance, β-cell function, and insulin sensitivity in 154 first-degree relatives of 55 patients with type-2 diabetes. The plasma glucose achieved at 1 h was normally distributed in normal control subjects, but 31 (20%) of relatives of type-2 diabetics had values above the normal distribution mean +2 SD. Insulin secretion, assessed from the first or second phase plasma-C-peptide responses, was significantly lower in the glucose-intolerant relatives than in normoglycaemic relatives of similar sex, age, and obesity. β-cell function, estimated by means of model analysis, was severely impaired in the glucose-intolerant relatives but was not impaired in the normoglycaemic relatives (geometric mean 41% and 109% of normal β-cell response, respectively). Reduced β-cell function was found with all degrees of glucose intolerance, whereas only the more severely hyperglycaemic relatives had impaired insulin sensitivity. This suggests that the primary defect in familial type-2 diabetes is β-cell dysfunction.