The 5-year incidence of myocardial infarction and claudication was examined in a group of middle-aged patients (n = 133, 70 men and 63 women) with newly diagnosed non-insulin-dependent diabetes and nondiabetic control subjects (n = 144, 62 men and 82 women). The effects of general risk factors, plasma insulin level, and lipoprotein abnormalities on the incidence of myocardial infarction and claudication were also evaluated by univariate analyses in both diabetic patients and nondiabetic subjects and by multivariate analyses combining both groups. The age-adjusted incidence of myocardial infarction was higher both in diabetic men (19.4%) and diabetic women (11.0%) than in nondiabetic men (3.2%, p = 0.009) and nondiabetic women (3.0%, p = 0.047). Similarly, the age-adjusted incidence of claudication was higher among the diabetic patients (20.3% vs. 8.0% for men, p = 0.06; 21.8% vs. 4.2% for women, p = 0.003). None of the general risk factors (i.e., low density lipoprotein [LDL] cholesterol, blood pressure, smoking, and high density lipoprotein [HDL] cholesterol) showed an association with the risk of myocardial infarction either in the diabetic or nondiabetic groups of subjects, but an ischemic electrocardiographic abnormality at the baseline examination predicted myocardial infarction in diabetic men. In univariate analyses in diabetic subjects, high serum total cholesterol, low HDL cholesterol, high very low density lipoprotein (VLDL) cholesterol, and high total, LDL and VLDL triglycerides, and in nondiabetic subjects, high VLDL cholesterol and LDL triglycerides were associated with the appearance of claudication. In multivariate analyses including both diabetic and control subjects, only diabetes had an independent association with myocardial infarction, whereas smoking, high LDL triglycerides or VLDL cholesterol, and high fasting plasma insulin showed independent relations to claudication. The present results indicate that changes in lipoprotein composition characteristic of non-insulin-dependent diabetes are atherogenic and increase the risk of atherosclerotic vascular disease. Furthermore, high plasma insulin might also be involved in atherogenesis, independent of lipoprotein abnormalities.