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Background. The epidermal growth factors amphiregulin (AREG) and heparin-binding epidermal growth factor (HB-EGF) are implicated in the pathogenesis of several autoimmune diseases, but their clinical and pathological roles in idiopathic inflammatory myopathy (IIM) are unclear. Methods. Serum AREG and HB-EGF levels were measured by ELISA in patients with IIM (n = 37), systemic sclerosis (n = 17), and rheumatoid arthritis (n = 10), and for seven age- and sex-matched healthy controls (HCs). Associations between serum AREG or HB-EGF levels and the clinical parameters were analyzed. Results. Serum AREG levels in IIM patients were significantly elevated compared to those in HCs (median, 20.7 and 10.7 pg/mL, respectively, p = 0.025). In particular, serum AREG levels in IIM patients with interstitial lung disease (ILD) were higher than those of HCs (22.4 pg/mL, p = 0.027). The disease duration in patients with elevated serum AREG levels was significantly shorter compared to those who had normal serum AREG levels (7 and 21 months, respectively, p = 0.0012). Serum HB-EGF levels were significantly increased in IIM patients with elevated CK levels (136.2 pg/mL, p = 0.020) and patients with anti-Mi-2 antibody (183.7 pg/mL, p = 0.045) compared to those in HCs (74.9 pg/mL). Conclusion. These results suggested that AREG could be a promising biomarker associated with early-phase IIM-related ILD, and that HB-EGF expression was associated with muscle injury and regeneration in IIM.