Relationships among islet cell antibodies (ICA), residual beta-cell function, and metabolic control were studied in 60 insulin-dependent diabetics (IDDs) of long duration (6 to 31 years). Sensitive C-peptide immunoreactivity (CPR) and ICA assays with limits of 0.017 nmol/L and 5 Juvenile Diabetes Foundation (JDF) U, respectively, demonstrated that baseline (0.16 +/- 0.02 nmol/L, mean +/- SE, n = 26), as well as maximum CPR values (0.34 +/- 0.05 nmol/L), during 100-g oral glucose tolerance tests (OGTT) in ICA-positive IDDs were significantly higher than corresponding values in ICA-negative ones (baseline values, 0.10 +/- 0.01 nmol/L, P less than .05; maximum values, 0.20 +/- 0.04 nmol/L, P less than .01, n = 34). Negative correlation was observed between increment of serum CPR and metabolic control indices, including fasting blood glucose (FBG) and HbA1c levels (P less than .05). In addition, ICA-positive insulin-dependent diabetes mellitus (IDDM) patients had lower values of FBG (8.2 +/- 0.4 mmol/L, P less than .01 v ICA-negative IDDs) and HbA1c (9.2% +/- 0.2%, P less than .05 v ICA-negative IDDs) than ICA-negative ones (FBG, 9.9 +/- 0.4 mmol/L; HbA1c, 9.8% +/- 0.2%). These results indicate that minute CPR responses to OGTT detected by sensitive methods may represent residual pancreatic beta cells, which may contribute to ICA generation and good metabolic control in IDDs of long duration.