Abstract Rationale: A pre-existing diagnosis of cirrhosis is clinically recognized as a risk factor for sepsis and sepsis-associated complications. However, the unique epidemiology, sepsis characteristics, and underlying mechanisms of immune dysregulation in sepsis among patients with cirrhosis remain incompletely understood. Comorbid conditions, including cirrhosis, may influence sepsis biology and host response, and thus identify specific subgroups with sepsis that may benefit from a personalized approach. Our primary objective was to identify clinical and biological characteristics that differ between patients with and without cirrhosis among patients presenting to the ICU with sepsis. Methods: We analyzed data from a prospective cohort of patients presenting to our center's ICU with sepsis, according to Sepsis-3 criteria. Pre-existing diagnosis of cirrhosis and other detailed comorbidity data were extracted from the electronic medical record. Subjects were followed for 6 days for the development of acute respiratory distress syndrome (ARDS) adjudicated according to the Berlin definition and acute kidney injury (AKI) adjudicated according to KDIGO creatinine and dialysis criteria, and for mortality at 30 days. Inflammatory, endothelial, and vascular injury proteins were measured via electrochemiluminescence multiplex array in plasma collected at ICU admission in a subset of patients. We determined associations of cirrhosis with ARDS, AKI, and mortality using multivariable logistic regression adjusting for pre-specified confounders. We tested differences in plasma protein levels by cirrhosis diagnosis using the Wilcoxon Rank-sum test. Results: We enrolled 2,692 subjects between 2008 and 2022, 371 (13%) of whom had a pre-existing diagnosis of cirrhosis. Patients with cirrhosis had higher severity of illness scores, were more likely to have an abdominal source of sepsis, and had more significant coagulation abnormalities relative to patients without cirrhosis (Table). In multivariate analysis, cirrhosis was associated with higher AKI risk (adjusted OR 1.92; 95% CI 1.43 to 2.53; P<0.001) and 30-day mortality (adjusted OR 1.39; 95% CI 1.09 to 1.78; P=0.007), but not ARDS risk (adjusted OR 1.15; 95% CI 0.82 to 1.61; P=0.42). Cirrhosis was associated with higher plasma levels of angiopoietin-2 (P<0.001), von Willebrand factor (P<0.001), and soluble thrombomodulin (P<0.001), as well as lower levels of interleukin (IL)-10 (P<0.001), IL-1β (P=0.008), and IL-1RA (P=0.036) (Table). There were no significant differences in levels of IL-6 (P=0.30). Conclusions: We identified associations between pre-existing cirrhosis and endothelial biomarker concentrations, AKI, and mortality in sepsis. Patients with pre-existing cirrhosis who develop sepsis may display a unique signature of endothelial dysfunction that requires targeted approaches.