To explore the clinical features, treatment and prognosis of patients with anti-melanoma differentiation-associated gene 5 (MDA5) positive dermatomyositis combined with rapidly progressive interstitial lung disease (RPILD). Clinical data, treatment process, and prognostic characteristics of 3 patients with anti MDA5 antibody positive dermatomyositis combined with RPILD admitted to our hospital from July 2020 to October 2021 were retrospectively analyzed. The discussion was performed after literature review. Among the 3 patients, 1 was male and 2 were females with an average age of (55.7 ± 2.1) years old and an average disease course of (3.8 ± 0.2) months. The main clinical manifestations were typical rash and progressive dyspnea. Serum muscle enzyme was increased. Serum anti-MDA5 antibody, anti-histaminoyl synthase antibody (Jo-1) and anti-Ro-52 antibody were all positive. The skin and muscle biopsies at the rash sites all indicated inflammatory changes. The imaging showed progressive worsening pulmonary interstitial fibrosis in the short term. All 3 patients were treated with hormone shock + immunoglobulin + cyclophosphamide, and 1 patient was treated with rituximab. The 3 patients died on the 27th, 37th, and 48th day after hospitalization, respectively. Moreover, 2 patients died of acute respiratory failure, and 1 patient died of septic shock. Anti-MDA5 positive dermatomyositis combined with RPILD is a disease with rapid progression, poor efficacy and high mortality rate. The main clinical manifestations are typical rash and progressive dyspnea, elevated serum muscle enzymes, and positive anti-MDA5 antibodies. In addition, the 3 patients simultaneously had positive anti- Jo-1 antibodies and anti-Ro-52 antibodies. Imaging shows progressive exacerbation of pulmonary interstitial fibrosis in the short term. Drug treatments mainly focused on hormone shock, immune regulation and targeted blockade. However, the drug treatments have failed to save the lives of the patients. Severe infection caused by immunosuppression after treatment is also an important cause of death. Early identification and early intervention as well as ECMO support and lung transplantation in the later stages of the disease may be effective ways to reduce mortality.