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Studies have compared proton pump inhibitors (PPI) with Histamine 2 receptor antagonists (H2RA) and placebo for upper gastrointestinal bleeding (UGIB) prophylaxis in mechanically ventilated patients. We conducted this meta-analysis to compare PPI with H2RA or placebo for UGIB prophylaxis in these patients. Our outcomes of interest were clinically important UGIB, overall UGIB, mortality, ventilator-associated pneumonia (VAP) and Clostridium difficile infection (CDI). We calculated pooled risk ratio (RR) with 95% confidence intervals (CI) for all outcomes. We included eight RCTs comprising 32,873 patients. Risk of clinically important UGIB was significantly lower in PPI group, RR (95%CI): 0.53 (0.32, 0.89). Risk of overall UGIB was also significantly lower in PPI group. There was no significant difference in mortality, VAP and CDI between groups. This meta-analysis demonstrates the superiority of PPI to H2RA and placebo for prophylaxis of UGIB in mechanically ventilated patients, without increasing the risk of adverse events.