<![CDATA[Stress-related mucosal disease (SRMD) remains a significant concern in intensive care, with mucosal damage often occurring within the first 24 hours of admission. While modern critical care practices and early enteral nutrition have reduced the incidence of clinically significant bleeding to approximately 2–3%, the consequences of such events—ranging from hemodynamic instability to prolonged mechanical ventilation—remain severe. Stress ulcer prophylaxis (SUP) is standard practice; however, the choice between proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) remains a subject of clinical debate. As newer data have emerged since 2022, there is a pressing need to re-evaluate whether the potent acid suppression of PPIs offers a genuine survival advantage or whether it introduces unnecessary infectious risks. A systematic search was conducted across PubMed, ScienceDirect, the Cochrane Library, and Scopus, covering literature from inception through 15 August 2025. This review specifically targeted geriatric populations (≥65 years) in acute care settings. The selection process involved rigorous screening using Rayyan software, identifying nine high-quality studies—including the landmark PEPTIC trial and several large-scale observational cohorts. Quality was assessed using the Cochrane RoB 2 tool for randomized trials and the Newcastle–Ottawa Scale for observational studies, ensuring a robust synthesis of contemporary real-world evidence. Analysis of the included studies revealed a complex trade-off between efficacy and safety. Regarding mortality, the evidence was largely neutral; the PEPTIC trial reported a 90-day mortality risk ratio of 1.05, and most observational cohorts similarly showed no clear survival benefit. In terms of efficacy, PPIs demonstrated superior ability to reduce clinically important gastrointestinal bleeding (GIB) in large-scale trials (RR 0.73 in the PEPTIC study), although this finding was not consistently replicated in observational data, where heterogeneity was high. Crucially, the “cost” of profound acid suppression became evident in safety outcomes. PPI use was associated with a higher incidence of *Clostridioides difficile* infection (CDI) and a trend toward increased hospital-acquired pneumonia. In contrast, H2RAs demonstrated a more favorable safety profile, with lower infectious complications and, in some settings, reduced healthcare resource utilization. The findings suggest that a “one-size-fits-all” approach to stress ulcer prophylaxis is no longer appropriate. While PPIs are effective in preventing major bleeding in high-risk patients—such as those with severe coagulopathy—they do not improve overall survival and may predispose vulnerable patients to serious infections. H2RAs emerge as a balanced alternative, offering adequate protection with fewer adverse effects. Clinicians should adopt an individualized SUP strategy, prioritizing PPIs for patients at the highest risk of hemorrhage while favoring H2RAs or early discontinuation in patients for whom the risk of infection and sepsis outweighs the potential benefit of gastrointestinal bleeding prevention.]]>
