This study was sought to compare in-hospital mortality rates applying PPIs vs H2RBs for stress ulcer prophylaxis. Researchers conducted a cluster crossover randomized clinical trial including a total of 26,982 individuals requiring invasive mechanical ventilation within 24 hours of ICU admission at 50 ICUs in 5 countries between August 2016 and January 2019. They compared two stress ulcer prophylaxis strategies (preferential use with PPIs vs preferential use with H2RBs). The primary endpoint included all-cause mortality within 90 days during the index hospitalization. Clinically important upper gastrointestinal bleeding, Clostridioides difficile infection, and ICU and hospital lengths of stay were considered secondary endpoints. A strategy of stress ulcer prophylaxis with the use of proton pump inhibitors vs histamine-2 receptor blockers resulted in in-hospital mortality rates of 18.3% vs 17.5%, respectively among ICU individuals requiring mechanical ventilation, a difference that did not reach the significance threshold. Nevertheless, research interpretation may be limited by a crossover in the use of the assigned medication.