OBJECTIVE: To describe the incidence of adverse events associated with intensive versus conventional therapy of insulin-dependent diabetes mellitus (IDDM) as implemented in the Diabetes Control and Complications Trial (DCCT). RESEARCH DESIGN AND METHODS: The DCCT was a randomized, controlled clinical trial conducted at 26 centers in the U.S. and 3 centers in Canada. All data were collected from patient notifications of events and/or standardized, quarterly interviews that were validated and analyzed at a data coordinating center as events per 100 patient-years. The 1,441 volunteers were between the ages of 13 and 39 with IDDM for 1–15 years. Average length of follow-up was 6.5 years (range 3–9). Subjects were randomly assigned to conventional or intensive diabetes treatment. RESULTS: The two treatment groups did not differ in mortality, major morbidity secondary to accidents, or ketoacidosis. However, intensive therapy was associated with a threefold increase in the risk of severe hypoglycemia (for hypoglycemia requiring assistance, the event rate per 100 patient-years was 61.2 in the intensive treatment group versus 18.7 in the conventional treatment group; for hypoglycemia involving coma or seizure, the rate was 16.3 vs. 5.4). Intensive therapy was also associated with a 73% higher risk of becoming overweight. There was a 46% reduction in the incidence of vaginitis in the intensive treatment group, but there were no significant differences in the rates of other infections. CONCLUSIONS: The major adverse effect of intensive therapy of IDDM is a threefold increase in the risk of severe hypoglycemia with potentially serious sequelae. An increased incidence of becoming overweight, the long-term significance of which has yet to be determined, was also observed. Because the results of the DCCT were attained in highly selected, healthy IDDM patients who received attentive clinical management and frequent health education, DCCT adverse event rates may not reflect incidence or prevalence rates that would be expected in nonselected populations or in other clinical settings.