ObjectiveTo investigate the clinical significance of levels of serum salivary Krebs von den Lungen 6 (KL-6) and matrix metalloproteinase-9 (MMP-9) in predicting the prognosis of patients with acute respiratory distress syndrome (ARDS). MethodsFrom January 2020 to December 2023, 100 ARDS patients who received treatment in our hospital were included as the study group, and 59 healthy professionals who underwent health checkup were selected as the control group. And the levels of serum KL-6 and MMP-9 were measured on the day of admission. According to the oxygenation index (OI) results, the study group was separated into mild group (38 cases), moderate group (33 cases), and severe group (29 cases); Based on 28-day intensive care unit (ICU) survival status, the study group was divided into a survival group of 69 cases and a death group of 31 cases. Enzyme-Linked Immunosorbent Assay (ELISA) method was applied to detect the levels of serum KL-6 and MMP-9. Pearson correlation was applied to analyze the correlation between serum KL-6 and MMP-9 levels and OI in the death group. Logistic regression was applied to analyze the influencing factors of prognostic mortality in ARDS patients. Receiver operating characteristic (ROC) curve was applied to analyze the predictive value of serum KL-6 and MMP-9 levels for prognostic mortality in ARDS patients. ResultsCompared with the control group, the levels of serum KL-6 and MMP-9 in the study group were notably increased, and the levels of serum KL-6 and MMP-9 in the severe ARDS group were notably higher than those in the moderate and mild groups. The levels of serum KL-6 and MMP-9 in the moderate group were notably higher than those in the mild group, the OI in the survival group was greatly higher than that in the death group, and the acute physiology and chronic health evaluationⅡ (APACHE II) score, KL-6, and MMP-9 in the survival group were greatly lower than those in the death group (P<0.05). Pearson analysis showed that serum KL-6 and MMP-9 levels were negatively correlated with OI (P<0.05). Logistic analysis showed that APACHE II score, KL-6, and MMP-9 were risk factors for prognostic mortality in ARDS patients (P<0.05). ROC curve showed that the AUC of serum KL-6 and MMP-9 levels in predicting prognostic mortality in ARDS patients was 0.809 and 0.816, respectively, with cutoff value of 510.44 U/ml and 317.15μg/L, respectively. The area under the ROC curve (AUC) predicted by the combination of the two was 0.935, greatly higher than that of KL-6 (Z=2.133, P=0.033) and MMP-9 (Z=2.164, P=0.030) alone. ConclusionsThe levels of serum KL-6 and MMP-9 in ARDS patients are greatly upregulated and increase with the severity of the disease. The combination of the two has certain predictive value for the prognostic mortality of ARDS patients.