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Histamine2-receptor blockers appear to be effective in preventing gastrointestinal bleeding in people with stress ulcers. Several meta-analyses of the effectiveness of anti-ulcer drugs have produced mixed results. Researchers reviewed 63 randomized clinical trials of anti-ulcer drugs in the prevention of overt and silent gastrointestinal bleeding. Histamine2-receptor blockers significantly reduced both overt and silent bleeding when compared to antacids, a placebo or no therapy. Sucralfate and antacids reduced overt bleeding compared to placebo or no therapy, but neither appeared more effective than histamine2-receptor blockers. However, sucralfate lowered the incidence of pneumonia when compared to antacids and histamine2-receptor blockers. In fact, histamine2-receptor blockers were associated with an increased incidence of pneumonia. Sucralfate appeared to reduce mortality rates when compared to antacids and histamine2-receptor blockers., Purpose.--To resolve discrepancies in previous systematic overviews and provide estimates of the effect of stress ulcer prophylaxis on gastrointestinal bleeding, pneumonia, and mortality in critically ill patients. Data identification.--Computedzed search of published and unpublished research, bibliographies, pharmaceutical and personal files, and conference abstract reports. Study Selection.--Independent review of 269 articles identified 63 relevant randomized trials for inclusion. Data Abstraction.--We made independent, duplicate assessment of the methodologic quality, population, intervention, and outcomes of each trial. Results.--The source of discrepancies between prior meta-analyses included incomplete identification of relevant studies, differential inclusion of non-English language and nonrandomized trials, different definitions of bleeding, provision of additional information through direct correspondence with authors, and different statistical methods. The current overview demonstrates that prophylaxis with [histamine.sub.2]-receptor antagonists decreases the incidence of overt gastrointestinal bleeding (odds ratio [OR], 0.58; 95% confidence interval [CI], 0.42 to 0.79) and clinically important bleeding (OR, 0.44; 95% CI, 0.22 to 0.88). There is a trend to- ward decreased overt bleeding when antacids are compared with no therapy Off@ 0.66; 95% CI, 0.37 to 1.17). [Histamine.sub.2]-receptor antagonists and antacids are associated with a trend toward lower clinically important bleeding rates than sucralfate is. There is a trend toward an increased risk of pneumonia associated with [histamine.sub.2]-receptor antagonists as compared with no prophylaxis (OR, 1.25; 95% CI, 0.78 to 2.00). Sucralfate is associated with a lower incidence of nosocomial, pneumonia when compared with antacids (OR, 0.80; 95% CI, 0.56 to 1.15) and [histamine.sub.2]-receptor antagonists (OR, 0.77; 95% CI, 0.60 to 1.01). Sucralfate is also associated with a reduced mortality rate (OR, 0.73; 95% CI, 0.54 to 0.97) relative to antacids and to [histamine.sub.2]-receptor antagonists (OR, 0.83; 95% CI, 0.63 to 1.09). Conclusions.--Our results emphasize the need for registries to include all randomized trials and demonstrate the importance of explicit methodology for systematic reviews. There is strong evidence of reduced clinically important gastrointestinal bleeding with [histamine.sub.2]-receptor antagonists. Sucralfate may be as effective in reducing bleeding as gastric pH-altering drugs and is associated with lower rates of pneumonia and mortality. However, the data are insufficient to determine the net effect of sucralfate compared with no prophylaxis. (JAMA. 1996;275:308-314)