Objective: This study was designed to investigate the relationship between plasma cortisol levels and stress ulcer following acute severe head injury. Subjects and Methods: The plasma cortisol levels were prospectively measured by radioimmunoassay in 68 patients following acute head injury. The diagnosis of stress ulcer was based on clinical evidence and was confirmed by endoscopic examination. Results: Patients with stress ulcer and gastrointestinal bleeding (n=30, 44.1%) were older than those without stress ulcer (38.2±7.9 vs 28.3±9.7, P<0.01). The combined rate of poor recovery and death in the stress ulcer group was significantly higher than in the non-ulcer group (70.0% vs 42.1%, P=0.02). On each of the first three days following the head injury, the average plasma cortisol levels in the stress ulcer group was higher than in the non-ulcer group (P<0.01). Univariate analysis showed a positive relationship between plasma cortisol at admission and stress ulcer (r= 0.329, P=0.01). Logistic regression analysis revealed plasma cortisol levels at admission (OR, 2.326, 95% CI: 1.982-2.466) and age (OR, 1.064, 95% CI: 0.861-1.219) were independent predictors for stress ulcer. Conclusions: Acute severe head injury is associated with a significant increase in plasma cortisol. Plasma levels of cortisol and age are independent predictors for stress ulcer following acute head injury.