The aim of this study was to investigate whether insulin resistance is independently associated with early manifestations of atherosclerosis. To this end, 176 normotensive offspring of type 2 diabetic patients were subjected to euglycemic-hyperinsulinemic clamp to assess insulin sensitivity. Early atherosclerosis was studied by ultrasonography of the common carotid artery. Of the total 176 subjects, 145 were glucose tolerant, 18 had impaired fasting glucose, and 13 impaired glucose tolerance. Univariate correlations showed that age, body mass index, waist, blood pressure, 2-h post-challenge glucose, fasting insulin, triglycerides, interleukin-6, fibrinogen and white blood cell count were significantly correlated with carotid intima-media thickness whereas HDL cholesterol and glucose disposal showed a negative correlation. A stepwise multivariate regression analysis including gender, age, waist circumference, smoking status, SBP, DBP, triglyceride, HDL cholesterol, 2-h post-challenge glucose, plasma IL-6, fibrinogen, white blood cell count, insulin-stimulated glucose disposal and fasting insulin showed that the four variables that remained significantly associated with carotid IMT were waist circumference, insulin-stimulated glucose disposal, white blood cell count, and diastolic blood pressure accounting for 33.7% of its variation. These findings support the concept that insulin sensitivity rather than plasma insulin levels is associated with early atherosclerosis in nondiabetic normotensive offspring of type 2 diabetic patients.