Objective: This study aimed to evaluate the predictive value of the neutrophil-to-lymphocyte ratio (NLR) and the systemic immune-inflammation index (SII) in forecasting rapidly progressive interstitial lung disease (RPILD) in patients with anti-melanoma differentiation-associated gene 5-positive dermatomyositis (anti-MDA5₊ ^DM).Methods: We retrospectively analyzed the clinical and laboratory data of 124 patients with anti-MDA5₊ ^DM. Cox regression analysis was employed to identify independent risk factors associated with the development of RPILD and mortality. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cut-off values for predicting adverse outcomes.Results: Among the 124 patients, 36 (29.03%) developed RPILD, and 39 (31.45%) died during the follow-up period. Multivariate Cox regression analysis identified elevated NLR was an independent risk factor for RPILD, while elevated SII was independently associated with mortality. The ROC curve analysis demonstrated that an NLR exceeding 6.118 serves as a significant predictor for RPILD, and an SII above 875.791 is indicative of increased mortality risk. Conclusion: NLR and SII are accessible, cost-effective, and reliable prognostic indicators for patients with anti-MDA5₊ ^{DM, providing valuable} guidance for clinical management and risk stratification.