Little is known of the natural history of nephropathy in type 2 (non-insulin-dependent) diabetes, yet type 2 diabetes is a major cause of end-stage renal disease in the United States. The incidence rate of heavy proteinuria was determined in Pima Indians participating in a longitudinal population study of diabetes and its complications. Heavy proteinuria was defined by a urine protein (g/liter) to urine creatinine (g/liter) ratio greater than or equal to 1.0 (greater than or equal to 113 mg protein/nmol creatinine), a level which corresponds to a urine protein excretion rate of about 1 g/day. The incidence rates of proteinuria in diabetic Pimas were 4, 12, 37, and 106 cases/1,000 person-years at risk in the periods 0 to 5, 5 to 10, 10 to 15, and 15 to 20 years after the diagnosis of diabetes. The cumulative incidence rates were 2%, 8%, 23%, and 50% at 5, 10, 15, and 20 years, respectively. The duration of diabetes, severity of diabetes as determined by the degree of hyperglycemia and type of treatment, and blood pressure were risk factors for proteinuria. The presence of heavy proteinuria was strongly associated with the development of renal insufficiency, defined by serum creatinine greater than or equal to 2.0 mg/dl (greater than or equal to 177 mumol/liter). The incidence of proteinuria in type 2 diabetes in Pima Indians was as high as that reported in type 1 diabetes in other populations and represents a frequent, serious complication of the disease.