Sixty-two mechanically ventilated patients were randomized into three study groups to compare the efficacy of sucralfate vs cimetidine and antacid regimens for the prevention of upper gastrointestinal tract bleeding. Only five study patients (8%) developed bright-red blood per nasogastric tube; four patients received the antacid regimen and one received cimetidine. None of the patients receiving sucralfate developed acute upper gastrointestinal tract bleeding. Bleeding was not severe enough in any patient to require endoscopy or surgery. There were no significant differences in the three groups when several major risk factors for gastrointestinal tract bleeding were analyzed, including sepsis, hypotension, steroid use, adult respiratory distress syndrome, gastric pH of 4 or less, previous peptic ulcer disease, peritonitis, and jaundice. A significantly higher incidence of acute renal failure was noted in the antacid-treated group when compared with the cimetidine and sucralfate groups. We find preliminary evidence that sucralfate is as efficacious as and more cost-effective than either cimetidine or antacids for prophylaxis of stress-related gastrointestinal tract bleeding in the critically ill ventilator-dependent patient.