Acute adrenal insufficiency (AI) is an uncommon disorder among critically ill burn patients, which can often go unrecognized. The goal of the current study is to identify risk factors for AI among patients who have sustained severe thermal injury. A case-control study was conducted among all adult patients admitted to the intensive care unit of the University of Alabama at Birmingham Burn Center during a 7-year period (1997-2003). All burn patients who developed AI were selected as cases (n = 26), and a random sample of those ICU patients who did not develop AI were selected as controls (n = 56). Two variables demonstrated significant independent associations with the risk of AI. Patients who developed AI were older than controls (50 vs. 46 years, respectively) and suffered a significantly greater area of thermal injury when compared with controls (mean percentage of total body surface area burned for cases and controls 45.5% and 25.4%, respectively). Over half (59.1%) of the patients with AI died compared with only 14.6% of controls (P < 0.0001). The development of AI appears to be associated with a greater TBSA burn and older age. After severe thermal injury, the diagnosis of AI substantially increases the risk of death. A better understanding of factors that predispose burn patients to AI may aid in earlier diagnosis, initiation of therapy, and improved outcomes.