Objective To explore the predictive value of Krebs von den Lungen-6 for the prognosis of patients with acute exacerbation of interstitial lung disease (AE-ILD).Methods A retrospective analysis was conducted on 154 patients with AE-ILD admitted to the Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Xuzhou Medical University, from June 2020 to December 2023. The patients were divided into death group (69 cases) and survival group (85 cases) based on their survival status 90 days after hospitalization. Serum KL-6 levels were measured using enzyme-linked immunosorbent assay, and clinical data were collected. Logistic regression analysis was used to analyze the risk factors affecting the prognosis of AE-ILD patients, and the value of serum KL-6 in predicting the prognosis of AE-ILD patients was analyzed using the receiver operating characteristic (ROC) curve; the Kaplan-Meier method was used to draw survival curves, and the comparison of survival rates was performed using the Log-rank test. Results The 90 day mortality rate of AE-ILD patients in this study was 44.8% (69/154). The death group had a higher proportion of patients with cardiovascular diseases, the use of anticoagulants during hospitalization, the use of non-invasive mechanical ventilation, and invasive mechanical ventilation than the survival group, and the levels of serum KL-6, LDH, CRP, PCT, and D-dimer were higher than those in the survival group (all P＜0.05), while the LYM and P/F ratio were lower than those in the survival group (both P＜0.05). Multivariate Logistic regression analysis showed that serum KL-6 (OR=3.358, 95%CI: 1.756～6.422) and invasive mechanical ventilation (OR=13.667, 95%CI: 2.241～51.586) were risk factors for poor prognosis in AE-ILD patients. The results of ROC analysis showed that the area under the curve (AUC) for serum KL-6 in predicting the prognosis of AE-ILD patients was 0.775 (95%CI: 0.700～0.850), the optimal cut-off value for serum KL-6 was 1259.5U/ml, with a sensitivity of 88.9% and a specificity of 64.7%. The patients were divided into two groups based on the optimal cut-off value of serum KL-6, and the survival period of each group was statistically analyzed, with a 90-day survival period as the upper limit. The survival curve showed that there was a significant difference between the high-level group (KL-6＞1 259.5 U/mL) and the low-level group (KL6＜1 259.5 U/mL) (P<0.05). Conclusion The level of serum KL-6 at admission is a risk factor affecting the prognosis of AE-ILD patients, and a serum KL-6 level greater than 1 259.5 U/mL helps to predict the prognosis of AE-ILD patients