ICAM-1 is one of the most important intercellular adhesion molecules involved in atherogenesis. Previous studies reported increased circulating ICAM-1 plasma levels in NIDDM patients with or without vascular complications. It has been suggested that an acute increase of plasma glucose may produce an oxidative stress in man, and in vitro studies have demonstrated that high glucose and free radicals induce cellular expression of ICAM-1. In this study, three different experiments were performed in nine NIDDM patients and in seven matched healthy controls: oral glucose tolerance test, antioxidant glutathione i.v. administration for two h, oral glucose tolerance test plus glutathione i.v. administration. Blood samples were drawn at -15 min and every 30 min from 0 to 180 min. During the oral glucose tolerance test, circulating ICAM-1 plasma levels significantly increased in both diabetic and normal subjects. Glutathione administration during the oral glucose tolerance test abolished this phenomenon. Glutathione administered alone significantly decreased circulating ICAM-1 plasma levels in diabetic patients, while no effect was observed in the normal subjects. These data suggest that hyperglycemia may induce an increase of circulating ICAM-1 plasma levels through an oxidative stress, and that the antioxidant glutathione counterbalances this effect. These data support the hypothesis of a causal relationship linking hyperglycemia, oxidative stress and atherogenesis in diabetes mellitus.