In the present study, we have compared and analyzed published data related to the pathogenesis of the large vessel disease in diabetes. The prevailing opinion appears to be that diabetes accelerates the mechanism that leads to development of classical atherosclerosis. However, as an alternative, we have amassed data that point to the presence of a diabetic macroangiopathy. This phenomenon comprises a constellation of nonatherosclerotic large vessel abnormalities. Today, we know that accumulation of periodic acid-Schiff (PAS)-positive material, as laminin, fibronectin, and type IV collagen, occurs together with hyaluronic acid and various types of connective tissue and calcium deposition. All these changes occur independent of the presence of atherosclerosis in the large vessels of diabetic patients. It seems to us that these observations emphasize that the concept of a specific diabetic macroangiopathy is a more fruitful working hypothesis than the usual theory of a link between atherosclerosis and diabetes. It provides a causal relationship (although the mechanism is unknown) between such changes and the abnormal metabolism in diabetes and a background for research strategy and tactics, aiming finally at the possibility of prevention and/or treatment of this common and dangerous disease.