Postprandial hyperglycemia is a powerful and independent risk factor for cardiovascular morbidity and mortality. The pathogenesis of vascular damage in the context of acute hyperglycemia is probably multifactorial, yet the overproduction of reactive oxygen species (ROS) is of particular importance. In normal subjects, acute hyperglycemia induces temporary endothelial dysfunction, reflected in an increase in arterial blood pressure. Because hyperglycemia, hyperinsulinemia, and hypertension are characteristic features of insulin resistance, it is hypothesized that during acute hyperglycemia in normal subjects, where similar changes are induced, transient insulin resistance occurs. The hypothesis that the frequency and grade of daily fluctuations of glycemia in conjunction with nutritional changes and lifestyle might participate in the chronic atherosclerotic process is an important issue. The effort to reduce postprandial hyperglycemia should be part of a strategy to prevent and treat cardiovascular disease in normal subjects and in prediabetic patients as well as in diabetic patients. In this review, we describe the mechanisms of transient endothelial dysfunction caused by acute hyperglycemia in normal subjects and suggest ways to treat it.