Gastrointestinal perforation in patients receiving glucocorticosteroid (GCS) therapy has been reported to have mortality rates as high as 100%. From 79 patients seen during a nine-year period, three groups were formed according to GCS dosage: group 1 (steroid perioperative coverage), group 2 (low-dose steroids, prednisone < 20 mg daily), and group 3 (high-dose steroids, prednisone ≥ 20 mg daily). Of 11 clinical presentation factors, only abdominal tenderness was consistently present in group 3. The mean delay from onset of symptoms to treatment for group 3 was 8.3 days and was in marked contrast to that for group 1 or 2, 1.7 and 2.2 days, respectively (p < 0.005). Mortality increased from 11.8% in group 1 to 13.3% in group 2 to 85% in group 3. High-dose GCS therapy decreased the clinical expression of peritonitis to the point that recognition and, therefore, treatment of gastrointestinal perforation were markedly delayed. In a patient receiving high-dose GCS, a high degree of clinical suspicion must accompany any new abdominal discomfort, and aggressive diagnostic efforts should be made to establish the cause. If abdominal pain persists, surgical exploration should be considered.