Abstract: Objective　To retrospectively analyze the clinical characteristics of patients with Talaromyces marneffei infection (TSM) complicated by osteolytic lesions in non-HIV infected individuals, aiming to improve the diagnosis and treatment of TSM in non-HIV patients. Methods　Clinical characteristics and laboratory data, of non-HIV adults diagnosed with TSM complicated by osteolytic destruction were collected from the People's Hospital of Liuzhou City from January 2019 to October 2023, covering nearly five years. Results　All 14 patients were healthy hosts without HIV infection or any underlying diseases. All patients had systemic manifestations such as fever, anemia, and weight loss, while 7 patients experienced bone pain. The initial symptoms mainly included neck mass, ulceration, and purulent discharge from the skin. Laboratory tests showed elevated white blood cell counts, C-reactive protein, and erythrocyte sedimentation rate. The CD4+ lymphocyte count ranged from 157 to 1 477 cells/μL, and CD8+ lymphocyte counts from 112 to 1 779 cells/μL, with CD4+/CD8+ ratios from 0.651 to 3.797. Pathogenic evidence was obtained from positive cultures of purulent or ulcerative secretions from the neck, chest, face, and joints in 9 cases, positive metagenome sequencing of mediastinal lymph nodes in 1 case, positive cultures of sputum and bronchoalveolar lavage fluid in 4 cases, and positive blood cultures in 1 case. Imaging findings showed osteolytic destruction involving any part of the skeleton. Nine patients improved with treatment, 2 died, 3 showed no improvement, and 6 cases were misdiagnosed as lung cancer or metastatic tumors. After antifungal treatment, 7 patients developed non-tuberculous mycobacterial infection, and 4 cases were co-infected with TSM and Mycobacterium tuberculosis. Conclusions　TSM complicated by osteolytic destruction is more common in non-HIV infected, with prominent manifestations of severe bone or joint pain. Early diagnosis is difficult, and it is prone to be complicated by non-tuberculous mycobacterial or Mycobacterium tuberculosis infection, leading to frequent misdiagnosed as cancer and tumors clinically.