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To determine the risk factors for development of severe hypoglycemia (defined as glucose <40 mg/dL) in critically ill patients and define the outcomes of this complication.Retrospective database review, including a case-control analysis that matched each patient with severe hypoglycemia with three controls.Adult intensive care unit of a university-affiliated community hospital.A total of 102 patients with at least one episode of severe hypoglycemia extracted from a series of 5,365 medical, surgical, and cardiac patients admitted consecutively between October 1, 1999, and June 15, 2006.A program of intensive glycemic monitoring and management, or tight glycemic control, was implemented on February 1, 2003; 2,666 patients were treated before and 2,699 after this date.Multivariable logistic regression analysis identified diabetes, septic shock, renal insufficiency, mechanical ventilation, severity of illness, reflected by Acute Physiology and Chronic Health Evaluation II score with the age component deleted, and treatment in the tight glycemic control period as independent risk factors for the development of severe hypoglycemia. Mortality was 55.9% among the 102 patients with severe hypoglycemia and 39.5% among the 306 controls (p = .0057). Multivariable logistic regression analysis identified severe hypoglycemia as an independent predictor of mortality for the entire cohort (odds ratio, 2.28; 95% confidence interval, 1.41–3.70; p = .0008). Among patients with severe hypoglycemia, only modified Acute Physiology and Chronic Health Evaluation II score and mechanical ventilation were identified as independent predictors of mortality. A sensitivity analysis was constructed that suggested that quadrupling the rate of severe hypoglycemia and doubling the mortality attributable to severe hypoglycemia would negate the survival benefit of tight glycemic control in this series.Case-control methodology and multivariable logistic regression analysis concurred that even a single episode of severe hypoglycemia was independently associated with increased risk of mortality. Safe implementation of tight glycemic control requires appropriate monitoring to reduce the risk of this complication.