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Corticosteroid supplementation based on plasma cortisol measurement was reported to decrease mortality in vasopressor-dependent critical illness.Random levels or maximal increments of plasma cortisol measured after short adrenal stimulation may predict mortality independent of concurrent organ dysfunction or sex, and corticosteroid supplementation may decrease mortality in vasopressor-dependent critical illness.An observational descriptive study.Critically ill patients receiving vasopressors for treatment of hemodynamic instability.Random levels (n = 522 patients) and maximal increments (n = 282 patients) of plasma cortisol were measured after 250 microg of adrenocorticotropic hormone was administered for short stimulation tests before patients received corticosteroid supplementation. The severity of acute illness was measured by sequential organ failure assessment.Hospital mortality.The overall mortality was 24%. A random plasma cortisol level of 15 microg/dL or less was associated with lower mortality than a random plasma cortisol level greater than 15 microg/dL in men (12% vs 26%, respectively; P.01) and women (13% vs 31%, respectively; P.01). A maximal plasma cortisol increment of 9 microg/dL or less increased mortality as compared with an increment greater than 9 microg/dL in men (31% vs 11%, respectively; P.01) but not in women (30% vs 29%, respectively; P = .8). Random levels and maximal increments of plasma cortisol did not influence hospital mortality predicted by the sequential organ failure assessment score. Corticosteroids were given to 244 patients (47%) without an effect on mortality (mortality rate of 27% for patients given corticosteroids vs mortality rate of 22% for patients who did not receive corticosteroids; P = .6). Corticosteroids did not influence mortality when plasma cortisol was a random level of 15 microg/dL or less (mortality rate of 14% for patients who received corticosteroids vs mortality rate of 10% for those who did not receive corticosteroids; P = .4) or when plasma cortisol was a maximal increment of 9 microg/dL or less (mortality rate of 30% for patients who received corticosteroids vs mortality rate of 31% for patients who did not receive corticosteroids; P = .9).Remote organ dysfunction and sex influenced mortality associated with cortisol levels measured in critical illness. Corticosteroid supplementation guided by arbitrary levels or increments of plasma cortisol in critical illness did not improve survival. Better guidelines for corticosteroid supplementation in critical illness should be developed to avoid potential adverse effects from unwarranted treatment.