Bleeding from stress-related mucosal disease (SRMD) in critically ill patients remains an important clinical management issue. Although only a small proportion (2% to 6%) of patients admitted to an ICU setting will bleed (1), a significant proportion exhibit the clinical risk factors, mainly mechanical ventilation for more than 48 hrs and the presence of a coagulpathy (2), that predict a higher risk of bleeding; furthermore, upper gastrointestinal mucosal lesions can be found in 75% to 100% of ICU patients (3). Although uncommon, stress-ulcer bleeding (SUB) is a severe complication as it is estimated that up to 50% patients will die, mostly from decompensation of an underlying condition or multiorgan failure (4). The use of SUB prophylaxis remains a matter of concern, its efficacy has been questioned with, in addition, some concerns about the risk of adverse events such as nosocomial pneumonia and clostridium difficile infection (5). Several medications have been assessed, including sucralfate, histamine-2 receptor antagonists (H2RAs), and protonpump inhibitors (PPIs). As H2RAs were shown to be superior to sucralfate (6), use of prophylactic pharmacotherapy comes down to opting for H2RAs or PPIs—a choice that has remained controversial as the underlying pathophysiology of SRMD differs from that of bleeding peptic ulcers, relating less on acid secretion and more on decreased mucosal blood flow, local ischemia, hypoperfusion, and reperfusion injury (3). In this issue of Critical Care Medicine, Dr. Alhazzani et al (7), report a systematic review and meta-analysis on the use of H2RAs or PPIs for stress ulcer prophylaxis in critically ill patients. The authors conclude that PPIs compared with H2RAs are more effective at reducing clinically important upper gastrointestinal bleeding (relative risk [RR] 0.36; 95% CI 0.19, 0.68) and overt upper gastrointestinal bleeding (RR 0.35; 95% CI 0.21, 0.59), without significantly increasing the risk of nosocomial pneumonia (RR 1.06; 95% CI 0.73, 1.52; p = 0.76). PPIs, however, appear to reduce neither ICU mortality nor length of stay, confirming and expanding findings of our meta-analysis published earlier this year (8). The major strength of this study