To examine the effects of age and duration and treatment of insulin-dependent diabetes (IDDM) on residual beta-cell function, we measured the fasting and Sustacal-stimulated serum C-peptide levels in 610 conventionally treated IDDM patients (age, 13-39 yr; duration of diabetes, 1-15 yr) during eligibility screening for the Diabetes Control and Complications Trial (DCCT). Fasting and stimulated C-peptide values were closely correlated (r = 0.83; P less than 0.001), and both declined with increasing duration of disease. However, among patients who had been diabetic for more than 5 yr, 11% (33 of 296) of adults compared with 0 of 75 adolescents (P less than 0.001) retained substantial insulin secretory capacity. Patients with stimulated C-peptide levels greater than 0.2 pmol/mL had a significantly lower mean fasting plasma glucose level [177 +/- 6 (+/- SEM) vs. 222 +/- 6 mg/dL; P less than 0.001), a smaller rise in glucose after Sustacal administration (151 +/- 5 vs. 184 +/- 3 mg/dL; P less than 0.001), and lower hemoglobin A1C (8.4 +/- 0.2% vs. 9.3 +/- 0.1%; P less than 0.001) than the patients with a stimulated C-peptide level of 0.05 pmol/mL or less, even though the C-peptide secretors were receiving less insulin (0.52 +/- 0.02 vs. 0.78 +/- 0.02 U/kg X day; P less than 0.001). To determine the effects of treatment of beta-cell function, 33 patients with stimulated C-peptide values between 0.2 and 0.5 pmol/mL at entry in the DCCT were restudied 1 yr after randomization to standard treatment (n = 15) or an experimental (n = 18) treatment designed to achieve and maintain near-normal glucose levels. Although C-peptide levels declined in both groups, experimental treatment was associated with slightly less of a decline in stimulated C-peptide values compared to Standard treatment. The results of C-peptide measurements in this large and well defined population of IDDM patients demonstrate that residual beta-cell function continues for a longer period of time in adults compared to adolescents with IDDM. This endogenous insulin secretion contributes significantly to metabolic control and may be prolonged by intensive insulin treatment regimens.