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The Surviving Sepsis Campaign Guidelines recommend stress ulcer prophylaxis for patients with severe sepsis who have bleeding risks. Although sepsis has been considered as a risk factor for gastrointestinal bleeding, the effect of stress ulcer prophylaxis has not been studied in patients with severe sepsis. Furthermore, stress ulcer prophylaxis may be associated with an increased risk of hospital-acquired pneumonia or Clostridium difficile infection. The aim of this study was to investigate the risks and benefits of stress ulcer prophylaxis for patients with severe sepsis.Retrospective cohort study.Five hundred twenty-six acute care hospitals in Japan.A total of 70,862 patients with severe sepsis.None.One-to-one propensity score matching created 15,651 pairs of patients who received stress ulcer prophylaxis within 2 days of admission and those who did not. Patient characteristics were well balanced between the two groups. No significant differences were seen between the stress ulcer prophylaxis group and the control group with regard to gastrointestinal bleeding requiring endoscopic hemostasis (0.6% vs 0.5%; p = 0.208), 30-day mortality (16.4% vs 16.9%; p = 0.249), and Clostridium difficile infection (1.4% vs 1.3%; p = 0.588). The stress ulcer prophylaxis group had a significantly higher proportion of hospital-acquired pneumonia (3.9% vs 3.3%; p = 0.012) compared with the control group.Since the rate of gastrointestinal bleeding requiring endoscopic hemostasis is not different comparing patients with and without stress ulcer prophylaxis, and the increase in hospital-acquired pneumonia is significant, routine stress ulcer prophylaxis for patients with severe sepsis may be unnecessary.