This study characterizes the hypothalamic-pituitary-adrenal axis function in patients with sepsis syndrome now known as systemic inflammatory response syndrome (SIRS). One hundred and thirteen patients with SIRS had their pituitary-adrenal axis tested with the use of a 250 µg IV ACTH stimulation test. No patient received corticosteroids prior to the ACTH stimulation test. Serum cortisol concentrations were measured prior to and 30 and 60 min after ACTH administration. 26% of the patients had bacteremia, 22% bacteruria, 22% AIDS, 17% renal failure, 15% diabetes, 13% severe liver disease, 8% GI bleed, 4% pancreatitis, 3% trauma and 1% classical Addison's disease. Several patients had more than one disorder. The overall mortality was 28%. Multivariate analysis identified that both the baseline cortisol concentration and delta cortisol concentration were significant indicators of mortality. Despite the fact that mortality was double in the bacteremic patients, the baseline cortisol concentrations were similar to the non-bacteremic patients (25.4 ± 1.9vs 25.1 ± 2.5 µg/dl). The only cortisol abnormality noted in the bacteremic patients was a significantly smaller delta cortisol response to ACTH (14.7 ± 2.2vs 18.9 ± 1.2 µg/dl;P<0.05). These data imply that bacteremic processes may alter the adrenal responsiveness to intravenous ACTH administration. Understanding the pathophysiological disturbances responsible for an impaired adrenal reserve may identify new treatment strategies for patients with bacteremia.