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The goal of this analysis was to characterize risk factors of patients who develop critical illness-related corticosteroid insufficiency (CIRCI) after acute burn injury. This is a retrospective, single-center case-control descriptive study performed at a regional burn unit at an academic medical center. Patients are adults with acute burn injury who developed CIRCI (cases) and sex-, age-, and burn size-matched controls. Cases were compared with controls based on clinical characteristics. Conditional logistic regression analysis was used to establish potential risk factors for cortisol insufficiency. CIRCI was diagnosed in 23 of 1183 patients during the period reviewed (1.9%); 159 controls were matched. CIRCI patients demonstrated significantly greater length of stay (35.1 vs 65.8 days, P ≤ .001), ventilator days (20.5 vs 33.2 days, P ≤ .001), and mortality (2.5% vs 17.4%, P ≤ .001) than controls. Patients with higher Charlson Comorbidity Index scores were more likely to develop cortisol insufficiency (odds ratio 1.58, 95% confidence interval 1.20–2.08), as were patients with inhalation injury (odds ratio 6.46, 95% confidence interval 2.01–20.72). Antibiotics and sedative/hypnotics analyzed by class were not significant. Multivariate conditional logistic regression analysis including Charlson Comorbidity Index and inhalation injury showed significant association of both dependent variables with CIRCI (pseudo-R2 = .32, P ≤ .001). Preexisting comorbidities and inhalation injury provide significant risks for development of CIRCI after acute burn injury. Acute burn patients who develop CIRCI have higher mortality, length of stay, and ventilator days than matched controls.