Objective: To analyze the clinical features and prognosis of patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (DM) with pulmonary symptom as the first manifestation. Methods: This study retrospectively reviewed 57 patients with anti-MDA5 antibody-positive DM who were admitted to the First Affiliated Hospital of Nanjing Medical University from August 2017 to October 2021. The patients were divided into pulmonary first symptom group (n=15) and non-pulmonary first symptom group (n=42) according to the first clinical manifestation. The general clinical data, laboratory test results, imaging findings and prognosis were compared between the two groups. Results: There were statistically significant differences in therapeutic regimens between the two groups (P<0.05). The levels of serum ferritin (SF) and C-reactive protein (CRP) in the pulmonary first symptom group were significantly higher than those in the non-pulmonary first symptom group, and the level of creatine kinase (CK) was significantly lower than that in the non-pulmonary first symptom group (P<0.05). The main chest CT sign of patients in the pulmonary first symptom group was patchy shadow, followed by ground-glass opacity, thread net, and consolidation. Few interlobular septal thickening, nodular opacity, honeycomb lung, and pleural effusion were observed. Multivariate logistic regression analysis showed that the levels of SF and CK were independent risk factors for anti-MDA5 antibody-positive DM with pulmonary symptoms as the first manifestations (P<0.05). The cumulative survival rate within 6 months after the onset was significantly different in the two groups (P<0.05). Conclusion: Glucocorticoids combined with immunosuppressive agents is the main therapeutic regimen for anti-MDA5 antibody-positive DM patients with pulmonary symptoms as the first manifestations. The patients have poor prognosis, and their clinical manifestations and imaging findings are diverse. The levels of SF and CK are related to anti-MDA5 antibody-positive DM with pulmonary symptom as the first manifestation, which indicates that they can be used as laboratory monitoring indicators.