Abstract Objectives Cardiac involvement in idiopathic inflammatory myopathies (IIM) is rare but potentially severe. Anti-mitochondrial M2 antibody (AMA-M2) has been implicated in cardiac involvement, but the association remains underexplored. This study aims to evaluate the clinical, pathological and prognostic features of AMA-M2 IIM. Methods This historic prospective cohort included IIM patients hospitalized at Peking Union Medical College Hospital between 2008 and 2020. Outcomes were prospectively collected through the Prospective Registry Of MyositIS (PROMIS) registry. Cox regression models were employed to identify risk factors of cardiac involvement and mortality. Results Among 987 IIM patients, 55 (6%) were AMA-M2 positive. These patients exhibited higher rates of PM (56% vs 23.5%, P < 0.001), and elevated baseline gamma-glutamyl transferase (78.0 vs 35.0, P < 0.001) and alkaline phosphatase (85.0 vs 64.0, P < 0.001). Throughout disease courses, AMA-M2-positive patients had significantly higher rates of cardiac involvement (60% vs 12.9%, P < 0.001), including arrhythmias (56%), heart failure (44%) and pulmonary hypertension (31%). Some of the muscle biopsies showed features consistent with immune-mediated necrotizing myopathy, cardiac biopsies demonstrating structural degeneration with minimal inflammation and liver biopsies confirming early-stage primary biliary cholangitis (PBC). Multivariate Cox analysis identified AMA-M2 positivity as an independent risk factor for cardiac involvement (hazard ratio 3.156, P < 0.001). Despite frequent cardiac manifestations, long-term survival did not differ between AMA-M2-positive and -negative patients (mean survival: 103.9 months vs 98.0 months, P = 0.86). Conclusion AMA-M2 positivity defines an IIM subgroup with significant cardiac involvement and an immune-mediated inflammatory muscle histology, but not necessarily worse long-term survival. These findings highlight the need for early recognition and tailored management of AMA-M2 IIM.