Hyperglycemia plays a primary causal role in the early vascular damage leading to diabetic retinopathy, but the intermediate biochemical mechanisms involved are not known. Because albumin modified by Amadori glucose adducts has been implicated in the pathogenesis of diabetic nephropathy, we investigated whether or not glycated albumin plays a similar role in diabetic retinopathy. We observed basement membrane thickening and an accumulation of basement membrane material in the capillaries of the outer plexiform layer of retinae from diabetic db/db mice compared with their nondiabetic db/m littermates. Both of these abnormalities were ameliorated by chronic (8 week) treatment with monoclonal antibodies that specifically recognize Amadori-modified glycated albumin (and not other glucose-modified or advanced glycation endproducts-modified proteins), despite the fact that the administration of these antibodies did not alter the glycemic status of the diabetic animals. Thus, albumin containing Amadori glucose adducts contributes to the pathogenesis of diabetic retinal vascular disease, and agents that neutralize or prevent the formation of excess glycated albumin in diabetes may offer prophylaxis against the early changes of diabetic retinopathy.