To determine the prevalence and predictors of, and the glucose responses after, nocturnal hypoglycemia, we studied 135 pediatric patients with insulin-dependent diabetes mellitus on 388 nights. The frequencies of blood glucose values less than 60, 50, and 40 mg/dl (3.3, 2.8, and 2.2 mmol/L) at 2 AM were 14.4%, 7.0%, and 2.1%, and at 6 AM were 6.7%, 2.6%, and 0.5%, respectively. Longer duration of diabetes, higher daily insulin doses, and lower glycosylated hemoglobin values were all significant but weak predictors of 2 AM hypoglycemia (glucose less than or equal to 60 mg/dl (less than or equal to 3.3 mmol/L). A 10 PM glucose concentration less than or equal to 100 mg/dl (less than or equal to 5.6 mmol/L) was present on 48% of nights with 2 AM glucose values less than or equal to 60 mg/dl (less than or equal to 3.3 mmol/L), but only 24% of nights with 10 PM blood glucose values less than or equal to 100 mg/dl (less than or equal to 5.6 mmol/L) were followed by 2 AM hypoglycemia. After treatment of 70 episodes of 2 AM glucose concentrations less than or equal to 60 mg/dl (less than or equal to 3.3 mmol/L), mean 6 AM glucose concentration was 95 +/- 6 mg/dl (5.7 +/- 0.3 mmol/L) and less than or equal to 100 mg/dl in 68.6%. In only 4.3% of these cases was the 6 AM glucose concentration greater than 200 mg/dl (greater than 11.1 mmol/L). Among patients who experienced 2 AM hypoglycemia, after-breakfast glucose values were not greater on days with 2 AM hypoglycemia than on days without it. These data indicate that 2 AM hypoglycemia is relatively common in patients with insulin-dependent diabetes mellitus, is frequently preceded by a 10 PM glucose value less than or equal to 5.6 mmol/L, and is less well predicted by other factors. Appropriate treatment of 2 AM hypoglycemia seldom results in either before-breakfast or after-breakfast blood glucose values greater than 200 mg/dl (greater than 11.1 mmol/L). Early-morning hypoglycemia is an uncommon cause of otherwise unexplained, prebreakfast hyperglycemia in children with insulin-dependent diabetes mellitus.