Background: Functional adrenal insufficiency (FAI) is associated with increased mortality and is defined as subnormal cortisol production during acute severe illness. Methods: After screening 200 adult patients admitted in the medical emergency unit of Mulago Hospital, Kampala, Uganda, 113 critically ill HIV-infected adults not receiving corticosteroids were enrolled after obtaining informed consent to determine the prevalence and factors associated with FAI. Results: Functional adrenal insufficiency, defined in this study as morning total serum cortisol level of = 25 mug/dl, was detected in 21 (19%) of 113 patients (95% CI 11-26%). Eosinophilia (>3%) occurred in 52% (11 of 21) patients with FAI compared to 24% (22 of 92) patients with normal adrenal function (p= 0.01). Factors predicting FAI on multivariate analysis were use of rifampicin and eosinophilia. The mortality rate among patients with FAI (19%) was not significantly different when compared to that among patients with a normal cortisol response (33%) (p=0.221). Hyponatremia, hypoglycemia, hyperkalemia, postural hypotension and the use of ketoconazole were not associated with FAI in this study. Conclusion: The diagnosis of FAI should be considered in severely ill patients with stage IV HIV disease using rifampicin or those found to have unexplained eosinophilia. Further studies to determine benefits of corticosteroids in critically ill HIV patients are needed in this setting