Less than a quarter of the patients with juvenile-onset IDDM develop diabetic nephropathy during the first 20 years of diabetes. To study the determinants of this complication, we selected patients who had come with newly diagnosed IDDM to the Joslin Clinic between 1967 to 1972, and we examined them in 1986 to 1988, that is, 15 to 21 years after onset of diabetes. Using a case control design we compared three groups of cases, that is, advanced nephropathy (N = 43), only microalbuminuria (N = 41), and hypertension alone (N = 17), with a group of controls who remained normoalbuminuric and normotensive despite the long duration of IDDM (N = 61). In comparison with controls, patients with advanced nephropathy had more parents with hypertension (odds ratio 3.8), higher Vmax values of Na/Li countertransport in red blood cells (odds ratio 10.0 for the highest tertile), and higher mean arterial pressure during adolescence and early adulthood (odds ratio 3.1 for those above the median). They also had significantly poorer glycemic control during their first 12 years of diabetes. Patients with hypertension alone were similar to those with advanced nephropathy with regard to markers of predisposition to hypertension but differed from them with regard to glycemic control, having the best glycemic control of all the study groups. Patients who developed only microalbuminuria during 15 to 21 years of IDDM (some of whom will progress to overt proteinuria later) did not differ significantly from controls with regard to predisposition to hypertension. In conclusion, predisposition to hypertension is a major risk factor for the development of advanced diabetic nephropathy and essential hypertension during the first 20 years of IDDM.