Objective: To investigate the clinical features of dermatomyositis (DM) and clinically amyopathic DM (CADM) patients with the presence of anti–melanoma differentiation–associated gene 5 (anti–MDA‐5) antibodies.Methods: We screened the serum anti–MDA‐5 antibody levels of 140 patients with various connective tissue diseases (CTDs), including 32 with DM and 32 with CADM, or idiopathic pulmonary fibrosis (IPF). The clinical courses of DM/CADM patients with a positive expression of anti–MDA‐5 antibodies were delineated.Results: Anti–MDA‐5 antibodies were detected at a significantly higher frequency in CADM patients than in DM patients (12 of 32 versus 3 of 32; P = 0.016), but were not detected in patients with other CTDs or IPF and healthy controls. Patients with a positive expression of anti–MDA‐5 antibodies developed significantly more skin ulcerations (12 of 15 versus 4 of 49; P < 0.001) and interstitial lung disease (ILD; 15 of 15 versus 31 of 49 [P = 0.003]) than those without anti–MDA‐5 antibodies. High‐resolution computed tomography scores of the MDA‐5–positive subset were increased compared with the MDA‐5–negative group (mean ± SD 117.7 ± 76.3 versus 54.4 ± 50.7; P = 0.004), and the scores correlated well with anti–MDA‐5 antibody levels (r² = 0.582, P = 0.029). The respiratory symptoms as well as skin ulcerations were dramatically improved in patients with anti–MDA‐5 antibody levels 500 units/ml were resistant to the treatment and died of respiratory failure in a short period of time.Conclusion: Anti–MDA‐5 antibody levels closely correlate with the severity of skin ulcerations, ILD, and the prognosis of the disease. Dynamic observation of serum anti–MDA‐5 antibody levels would be helpful in predicting the course of ILD and facilitating better therapeutic targeting.