Abstract: Objective To investigate the correlations of serum levels of NOD-like receptor family CARD domain containing 3 (NLRC3) and extracellular matrix protein 1 (ECM1) with the development of acute respiratory distress syndrome (ARDS) in patients with sepsis. Methods A total of 133 patients with sepsis were enrolled in sepsis group, and 80 healthy individuals during the same period were included in control group. The sepsis group was further divided into ARDS group (52 cases) and non-ARDS group (81 cases) based on the presence or absence of ARDS. Serum levels of NLRC3 and ECM1 expression were measured using enzyme-linked immunosorbent assays (ELISA). Multivariate Logistic regression analysis was used to identify factors associated with the development of ARDS in sepsis patients. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive value of serum NLRC3 and ECM1 levels for ARDS in sepsis patients. Results Compared with the control group, the sepsis group had significantly lower serum NLRC3 level and higher ECM1 level (P<0.05). The incidence of ARDS in the 133 sepsis patients was 39.10% (52/133). Compared with the non-ARDS group, the ARDS group had significantly lower serum NLRC3 level and higher ECM1 level (P<0.05). Independent risk factors for the development of ARDS in sepsis patients were increased Sequential Organ Failure Assessment (SOFA) score, elevated blood lactate level and increased ECM1 level, while increased NLRC3 level was an independent protective factor (P< 0.05). The area under the curve for the combined prediction of serum NLRC3 and ECM1 expression in sepsis patients with ARDS was 0.887, which was greater than 0.811 and 0.792 predicted by serum NLRC3 and ECM1 expression alone (P<0.05). Conclusion Decreased serum NLRC3 level and increased ECM1 level are closely associated with the development of ARDS in sepsis patients. The combined assessment of serum NLRC3 and ECM1 level has a high predictive value for ARDS in sepsis patients.