BACKGROUND: Anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis (DM) is a distinctive subtype of DM that carries a significant risk of interstitial lung disease (ILD). The mechanisms remain elusive. OBJECTIVES: To explore the role of the type I interferon (IFN) system in the pathogenesis of anti-MDA5 DM. METHODS: Twenty patients with anti-MDA5 DM were studied and compared with patients with anti-aminoacyl-tRNA synthetase (ARS) DM (n = 10) and autoantibody-negative patients with DM (n = 20). The levels of inflammatory cytokines, B-cell-activating factor (BAFF) and Krebs von den Lungen (KL)-6 in blood were tested by enzyme-linked immunosorbent assay and multiplex assays. Expressions of transcripts for IFN-associated sensors and type I IFN-inducible genes in peripheral blood mononuclear cells (PBMCs) were detected by real-time polymerase chain reaction. Expressions of the signal transducer and activator of transcription (STAT)1, interferon-stimulated gene (ISG)15 and MxA proteins in skin lesions were analysed by immunohistochemistry. RESULTS: Plasma IFN-α levels were significantly increased in patients with anti-MDA5 DM. PBMCs from patients with anti-MDA5 DM showed significant upregulation of the TLR3, TLR7, IFIH1 and DDX58 genes, as well as serial IFN-inducible genes. Skin biopsies from patients with anti-MDA5 DM were characterized by strong expression of the STAT1, ISG15 and MxA proteins. In the patients with anti-MDA5 DM and ILD with high IFN-α production, there was a positive quantitative correlation between IFN-α and BAFF (r(s) = 0·63, P = 0·044). In addition, the higher levels of BAFF paralleled the higher concentrations of KL-6 (r(s) = 0·86, P = 0·0012). CONCLUSIONS: Our data confirm the aberrant activation of the type I IFN system in anti-MDA5 DM. Overproduction of IFN-α linked with BAFF may be implicated in the development of ILD.