ObjectiveWhereas the antifungal azole ketoconazole interferes with steroidogenesis and can cause adrenal insufficiency, fluconazole in standard doses is thought to not interfere with cortisol production. The objective was to evaluate the effect of high-dose fluconazole therapy on adrenal function in critically ill patients in an intensive care setting.DesignDescriptive case reports.SettingMedical intensive care unit in a university hospital.PatientsTwo patients, a 77-yr-old man (case 1) with esophageal cancer and a 66-yr-old woman (case 2) with multiple organ failure developed reversible adrenal insufficiency temporally related to the institution and withdrawal of high-dose fluconazole.InterventionsShort cosyntropin (adrenocorticotropic hormone; ACTH) stimulation tests.Measurements and Main ResultsTwo days after high-dose fluconazole in case 1, the serum ACTH level was 121 pg/mL (normal range is 9–52 pg/mL), and the peak cortisol after ACTH stimulation was 15.5 &mgr;g/dL (normal response is ≥18 &mgr;g/dL). Eleven days after discontinuation of fluconazole, the peak cortisol level after ACTH stimulation was 43.4 &mgr;g/dL. Twenty-four hours after high-dose fluconazole in case 2, an ACTH stimulation test had a low peak serum cortisol of 16.8 &mgr;g/dL. Fluconazole was withdrawn, and 5 days later, the peak stimulated cortisol was 20.6 &mgr;g/dL.ConclusionsAlthough fluconazole is the therapy of choice for patients in the intensive care setting withCandidainfections, two patients with multiple organ failure who received high-dose fluconazole appeared to develop adrenal insufficiency. Although preliminary and anecdotal, these data suggest a need to further investigate the possibility that high-dose fluconazole might cause adrenal insufficiency in already compromised critically ill patients.