Plasma prorenin, but not renin, is elevated in long-standing diabetes mellitus. Nephropathy and autonomic neuropathy have been implicated as causes. However, we found no arteriovenous difference in prorenin across the kidney, despite high levels of circulating prorenin and a very low renal plasma flow, in five diabetics with combined end-stage nephropathy and proliferative diabetic retinopathy. Moreover, plasma prorenin was normal in 16 non-diabetics with autonomic neuropathy. The presence of a high level of prorenin was closely associated with the presence of diabetic retinopathy, particularly the proliferative type, in 223 consecutive patients. This association was independent of insulin requirements, metabolic control and of the presence of nephropathy or neuropathy. These data are evidence that part of the elevated plasma prorenin in diabetics is produced by an extrarenal source and that perhaps the eye affected by diabetic retinopathy is that source.