Context: Both excessive and insufficient activation of the hypothalamic-pituitary-adrenal axis in response to critical illness is associated with increased mortality. Objective: The objective of the study was to study the effect of intensive insulin therapy, recently shown to reduce mortality and morbidity of critically ill patients, on the cortisol response to critical illness. Design: This was a preplanned subanalysis of a large randomized, controlled study measuring serum total cortisol, cortisol-binding globulin, and albumin and calculating free cortisol levels. Setting: The study was conducted at a university hospital surgical intensive care unit. Patients: Four hundred fifty-one critically ill patients dependent on intensive care for more than 5 d and 45 control subjects matched for gender, age, height, and weight participated in this study. Intervention: The intervention was strict blood glucose control to normoglycemia with insulin. Results: Total and calculated free cortisol levels were equally elevated upon admission in both patient groups and thereafter were lower in intensive insulin-treated patients. Lower cortisol levels statistically related to the outcome benefit of intensive insulin therapy. Cortisol-binding globulin levels and structure were affected by critical illness but not insulin therapy, and neither were albumin levels. Administration of hydrocortisone in so-called replacement dose resulted in severalfold higher total and free cortisol levels, indicating that reevaluation of the doses used is warranted. Conclusions: Lower serum cortisol levels in critically ill patients receiving intensive insulin therapy statistically related to improved outcome with this intervention. The lower cortisol levels were not related to altered cortisol-binding capacity. Copyright