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Introduction: Sepsis-related ARDS is a life-threatening complication in critically ill patients. Endothelial cell activation and dysfunction have key roles in the pathophysiology of ARDS. Circulating endothelial cell (CEC) count as a marker of endothelial damage has been poorly studied in this setting. Hypothesis: CEC count may be elevated in patients with sepsis-related ARDS compared to those with severe sepsis or septic shock without respiratory failure. Methods: CEC enumeration was performed by indirect immunofluorescence using CD146-driven immunomagnetic isolation and a subsequent confirmatory step with Ulex-Europaeus-Lectin-1 staining according to a consensus isolation methodology. Arterial blood samples were drawn in 27 ARDS patients, 12 septic control patients, 13 non-septic control patients and12 healthy volunteers. Of the ARDS patients, 63% were graded as moderate or severe according to the recent Berlin definition. Demographic data, hemodynamic variables and prognostic variables (PaO2/FiO2 [P/F] ratio, 28-day survival, blood lactate, APACHE II and SOFA scores) were also recorded. Measurements were performed between 12-24 h after ICU admission and onset of sepsis.Median values (interquartile range) were compared using a Mann-Whitney test and correlations between CEC count and prognostic variables were analyzed. All tests were bidirectional and a p < 0.05 was considered significant. Results: The median CEC count in patients with moderate and severe ARDS was significantly higher compared to that in septic patients without ARDS [27.2 (17.9-49.4) cells/ml vs 17.1 (9.6-21.9) cells/ml, p< 0.01]. Patients with severe sepsis or septic shock had elevated CEC counts compared to non-septic patients [19.6 (14.2-30.6) cells/ml vs 10.8 (5.7-13.2) cells/ml, p<0.01]. In healthy volunteers, the CEC count was significantly lower than in critically ill patients [1.8 (0.4–3.7) cells/ml vs 17.9 (10.7-28.5) cells/ml, p<0.01]. None of the prognostic variables was significantly correlated with CEC count. Conclusions: CEC count is significantly higher in patients with moderate and severe ARDS than in non-ARDS septic and non-septic ICU patients. This finding highlights the importance of endothelial damage in ARDS.