A total of 1,441 patients with IDDM were randomly assigned to receive either intensive (n = 711) or conventional (n = 730) diabetes therapy in the Diabetes Control and Complications Trial (DCCT). The patients were followed for an average of 6.5 years. Subjects were instructed to report all episodes of suspected severe hypoglycemia to their health care team. In addition, at quarterly follow-up visits, each subject was asked about the occurrence of severe hypoglycemia. There were 3,788 episodes of severe hypoglycemia (requiring assistance); 1,027 of these episodes were associated with coma and/or seizure. A total of 65% percent of patients in the intensive group vs. 35% of patients in the conventional group had at least one episode of severe hypoglycemia by the study end; the overall rates of severe hypoglycemia were 61.2 per 100 patient-years vs. 18.7 per 100 patient-years in the intensive and conventional treatment groups, respectively, with a relative risk (RR) of 3.28. The relative risk for coma and/or seizure was 3.02 for intensive therapy. The increased risk with intensive treatment persisted over each of the 9 years of follow-up in the DCCT and over the calendar years 1984-1993 during which the study was conducted. When baseline patient characteristics were examined for effects on the risk of severe hypoglycemia, the relative risk of hypoglycemia for intensive versus conventional treatment was > or = 2 for all subgroups. Several subgroups defined by baseline characteristics, including males, adolescents, and subjects with no residual C-peptide or with a prior history of hypoglycemia, had a particularly high risk of severe hypoglycemia in both treatment groups. Analyses of the cumulative incidence of successive episodes indicated that intensive treatment was also associated with an increased risk of multiple episodes within the same patient (e.g., 22% experienced five or more episodes of severe hypoglycemia within the first 5 years of follow-up vs. 4% in the conventional group). Within both treatment groups, patients who experienced severe hypoglycemia were at increased risk of subsequent episodes. Approximately 30% of patients in each group experienced a second episode within the 4 months following the first episode of severe hypoglycemia. Within each treatment group, the number of prior episodes of hypoglycemia was the strongest predictor of the risk of future episodes, followed closely by the current HbA1c value. After adjustment for the current quarterly HbA1c level, intensive treatment was still associated with a significantly increased risk of hypoglycemia, indicating that the increased risk with intensive treatment is not completely explained by differences in HbA1c values.