This large prospective study was conducted to assess the predictive value of the homeostasis model assessment of insulin resistance (HOMA-IR) for primary cardiovascular risk in middle-aged Japanese men. A total of 2,548 nondiabetic men aged 35 to 59 years were followed for 11 years. A positive relationship between HOMA-IR and the risk of a first-ever cardiovascular event was observed after adjusting for major cardiovascular risk factors. More specifically, the hazard ratio associated with a one standard deviation (0.61) increment in log-transformed HOMA-IR was 1.51 (95% CI: 1.13-2.02). Similar positive relationships were observed for coronary events and strokes. Moreover, insulin resistance with compensatory hyperinsulinemia was found to have a distinct effect on the development of cardiovascular disease compared to other relevant metabolic disorders. Thus, these results suggest that HOMA-IR is a useful index to predict cardiovascular risk independently of traditionnal cardiovascular risk factors.