The frequency of symptomatic hypoglycemia was determined prospectively over an 18-mo period in 147 children and adolescents with diabetes mellitus. All patients were treated with two daily injections of insulin. The data were analyzed to determine the relationship between episodes of symptomatic hypoglycemia and blood glucose control as assessed by hemoglobin A1c measurements. There were 542 patient visits during the study period. During each clinic visit, patients were separated into one of four hypoglycemic categories based on the medical history since the preceding visit. These categories were: no reactions, mild to occasional reactions, mild to frequent reactions, and severe reactions. Reactions were considered severe if they were characterized by altered central nervous system function or prolonged sympathetic nervous system symptoms. Forty-seven percent of the patients reported at least one reaction during the 18-mo study period, but only 4% (i.e., 6 out of 147 patients) reported severe reactions. The mean hemoglobin A1c level was significantly lower in patients who reported reactions than in patients who did not report reactions [hemoglobin A1c values (x¯ ± SEM) = 7.78 ± 0.1% vs. 9.48 ± 0.1%, respectively; P > 0.001]. The severity of hypoglycemia was inversely related to the degree of altered blood glucose control; episodes of frequent or severe symptomatic hypoglycemia occurred almost exclusively in patients with well-controlled diabetes as reflected in their near-normal hemoglobin A1c levels. There were no significant differences in mean insulin dose/kg, age, or duration of diabetes comparing patients in the four hypoglycemic categories. The results indicate that the hemoglobin A1c level can be a useful clinical guide to identify patients who are most likely to develop serious symptomatic hypoglycemia.