Abstract: Objective To explore the clinical predictive value of the early modified ROX (mROX) index for short-term prognosis in patients with acute exacerbation of interstitial lung disease (AE-ILD). Methods Retrospective analysis was performed on clinical data from AE-ILD patients(n=149) who were admitted to the Affiliated Hospital of Xuzhou Medical University from January 2022 to December 2024. According to their 28-day survival status, the patients were divided into two groups: a death group(n=65) and a survival group(n=84). General information and baseline data were collected, and their mROX indices at admission and 24 h after admission were recorded. Univariate Cox regression analysis was conducted to screen potential risk factors. Furthermore, a multivariate Cox proportional hazards model was constructed to determine independent predictors of in-hospital mortality in AE-ILD patients. Restrictive cubic splines (RCS) were used to evaluate the relationship between mROX index and 28-day mortality in AE-ILD patients. Receiver operating characteristic (ROC) curves were plotted to investigate the predictive value of the mROX index for 28-day mortality and to calculate the optimal cutoff value. Kaplan-Meier survival curves were drawn for patients with different 24-hour mROX index levels. Results The mROX index at admission (6.8±3.6) and at 24 hours 5.2 (3.8, 6.5) in the death group were both significantly lower than those in the survival group (P<0.05). Multivariate Cox proportional hazards regression analysis showed that the mROX index at admission (HR=0.76, 95%CI: 0.71-0.81, P<0.05) and at 24 hours (HR=0.42, 95%CI: 0.34-0.52, P<0.05) were independent risk factors for 28-day mortality in AE-ILD patients. The area under the ROC curve for the 24-hour mROX index predicting 28-day mortality in AE-ILD patients was 0.940 (95%CI: 0.921-0.957, P<0.05), with an optimal cutoff value of 8.89. RCS analysis revealed a nonlinear positive correlation between the 24-hour mROX index and the risk of in-hospital mortality in AE-ILD patients (P<0.05). When the 24-hour mROX index was >8.89, the risk of death significantly decreased with increasing mROX index (nonlinear test P<0.001). Conclusions A decrease in the 24-hour mROX index is associated with an increased 28-day mortality in AE-ILD patients. The 24-hour mROX index has good predictive value for 28-day mortality in these patients.