Stress ulcer syndrome, the occurrence of acute upper gastrointestinal bleeding or perforation from stress-related mucosal damage, is a significant cause of morbidity and mortality in critically ill patients. The mortality rate in critically ill patients who have bled from stress ulcers ranges from 50 to 77 percent, whereas the mortality rate for similar patients without stress ulcer bleeding ranges from 9 to 22 percent. The mortality rate may be as high as 90 percent in patients with clinically overt bleeding; as many as one-third of these deaths can be directly related to bleeding. Prophylactic therapy for prevention of stress ulcer bleeding is based on three premises: (1) morbidity and mortality related to stress ulcer syndrome are significant; (2) the population at risk can be identified prior to bleeding; and (3) therapy that decreases gastric acidity or improves gastric mucosal defense mechanisms will prevent ulcer formation or progression to bleeding. A review of prospective clinical studies utilizing prophylactic therapy in critically ill patients and patients undergoing surgery revealed a 17 percent overall bleeding rate for placebo groups compared with lower bleeding rates for antacid- and histamine (H 2)-receptor-antagonist-treated groups (4 and 7 percent, respectively). Studies varied greatly in definition of bleeding, dosage regimens, and gastric pH goals. The need to measure gastric pH during treatment is controversial, and the optimal pH goal and the length of time for which it must be maintained remain unknown. Controversy exists as to the best therapeutic option for prophylaxis of stress ulcer syndrome, but when prevention of clinically significant bleeding is the therapeutic goal, antacids and H 2-receptor antagonists appear to be equally efficacious.