Background <p>Sepsis is the leading cause of death in critically ill patients, with an in-hospital mortality rate of approximately 25% to 40%. Coagulation activation serves as an initial factor to the progression of sepsis into multiple organ dysfunction syndrome (MODS). Therefore, anticoagulant therapy may be beneficial. Both preclinical experiments and clinical studies have evaluated the protective effect of nafamostat mesilate (NM) in sepsis. However, there is still a lack of randomized controlled trials (RCTs) to further confirm the therapeutic effect and safety of NM in sepsis patients.</p> Methods <p>This multicenter, double-blind, RCT was designed to recruit 778 subjects who met Sepsis 3.0 criteria. Participants will be randomly assigned (1:1) to receive either intravenous administration of NM or glucose along with standard treatment. The primary outcome is the all-cause mortality rate in the intensive care unit (ICU), and the secondary outcomes include the improvement in SOFA scores, changes in Japanese Association for Acute Medicine (JAAM)/International Society on Thrombosis and Hemostasis (ISTH) scores, 28-day all-cause mortality rate, and the incidence of adverse events. The allocation will remain concealed from investigators, participants, and statisticians to maintain blinding.</p> Discussion <p>The EASNMS trial aims to assess the efficacy and safety of NM for treating sepsis across various regions in China. As an additional treatment option, NM may potentially enhance the prognosis of sepsis patients.</p> Ethics and dissemination <p>Ethical approval has been obtained from all ethics committees of the involved centers. The findings of this study will be shared in peer-reviewed journals and will be presented at conferences.</p> Trial registration <p>ClinicalTrials.gov NCT06078839. Registered on September 20, 2023.</p>