The relationship of early retinal changes and subclinical proteinuria to duration and metabolic regulation of insulin-dependent diabetes was studied in 67 children. Retinopathy was found in 25 patients and occurred almost exclusively (96%) in those with duration of disease longer than five years. Glomerular filtration rate was normal or increased in all patients. Urinary excretion of beta 2-microglobulin, albumin, transferrin, and IgG was significantly increased in patients, as compared with controls, whereas serum concentrations of these proteins were generally normal. The mechanisms responsible for the hyperexcretion of both large and small proteins are unclear but probably involve both glomerular and tubular dysfunction. Increased urinary protein excretion occurred independently of duration of disease. Retinopathy but not microproteinuria was more common in patients with glycosylated hemoglobin greater than 11% and in those with duration of disease longer than five years. Although a significant association was found between retinopathy and the hyperexcretion of one or more of the large molecular weight proteins, the weight of the evidence suggests that these two sequelae of diabetes differ in their pathogenesis. Long-term follow-up of these patients may provide insight as to their risk of developing more serious retinopathy or nephropathy, and whether good glycemic control may protect against these complications of insulin-dependent diabetes.