Introduction: Identification of risk factors for diminished cortisol response to adrenocorticotrophic hormone (ACTH) in the critically ill could facilitate recognition of relative adrenal insufficiency in these patients. Therefore, we studied predictors of a low cortisol response to ACTH. Methods: A retrospective cohort study was conducted in a general intensive care unit of a university hospital over a three year period. The study included 405 critically ill patients, who underwent a 250 μg ACTH stimulation test because of prolonged hypotension or need for vasopressor/inotropic therapy. Plasma cortisol was measured before and 30 and 60 min after ACTH injection. A low adrenal response was defined as an increase in cortisol of less than 250 nmol/l or a peak cortisol level below 500 nmol/l. Various clinical variables were collected at admission and on the test day. Results: A low ACTH response occurred in 63% of patients. Predictors, in multivariate analysis, included sepsis at admission, low platelets, low pH and bicarbonate, low albumin levels, high Sequential Organ Failure Assessment score and absence of prior cardiac surgery, and these predictors were independent of baseline cortisol and intubation with etomidate. Baseline cortisol/albumin ratios, as an index of free cortisol, were directly related and increases in cortisol/albumin were inversely related to disease severity indicators such as the Simplified Acute Physiology Score II and Sequential Organ Failure Assessment score (Spearman r = -0.21; P < 0.0001). Conclusion: In critically ill patients, low pH/bicarbonate and platelet count, greater severity of disease and organ failure are predictors of a low adrenocortical response to ACTH, independent of baseline cortisol values and cortisol binding capacity in blood. These findings may help to delineate relative adrenal insufficiency and suggest that adrenocortical suppression occurs as a result of metabolic acidosis and coagulation disturbances.