Background: Limb-girdle muscular dystrophy R2 (LGMD R2) is most frequently misdiagnosed as immune-mediated necrotizing myopathy (IMNM). This study aimed to compare the clinicopathological data of IMNM and LGMD R2 to find distinguishing features. Methods: We retrospectively reassessed the medical data of patients with IMNM (n = 41) and LGMD R2 (n = 8) treated at Tongji Hospital from January 2017 to December 2021. Results: In our cohort, patients with LGMD R2 had a longer interval of onset to first visit, mild muscle weakness with late upper limb involvement, less myalgia, no cervical muscle weakness or dysphagia, no extramuscular organs affected except cardiac involvement, and lack of various autoantibodies, such as antinuclear antibodies. These features were completely reversed in IMNM. Moreover, thigh MRIs showed that muscle edema prominently affecting the adductor magnus was a characteristic of IMNM, while extensive fatty replacement was more common in LGMD R2 (p = 0.0086). Necrotic myofibers presented in both entities (p = 0.1693), while features such as ring/whorled and splitting myofibers were more often found in LGMD R2 (p = 0.0112 and p < 0.0001, respectively). Conversely, sarcoplasmic p62 expression was more pronounced in IMNM (p < 0.05). There were 4 of 8 (50%) patients with LGMD R2 initially considered as seronegative IMNM, and therefore unnecessarily treated with immunosuppressive drugs. Insufficient recognition of the early clinical, imaging, and histopathological features of LGMD R2 is the main reason for misdiagnosis. Conclusions: These findings may help clinicians differentiate seronegative IMNM and LGMD R2, reducing early misdiagnosis and mismanagement. Particularly, prominent adductor magnus edema on MRI and abundant p62 staining seem to be good markers for IMNM, while the presence of splitting myofibers is a crucial clue to early hereditary myopathy, including LGMD R2.