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Mycobacterium persicum (M. persicum) is a nontuberculous mycobacterium that predominantly affects the lungs, causing pulmonary lesions, and is readily misdiagnosed as tuberculosis. Here we report a 48-year-old man with AIDS and M. persicum pulmonary disease who was initially misdiagnosed with pulmonary tuberculosis and received standard anti-TB therapy, yet showed no radiological or clinical improvement. Sputum specimens were subsequently subjected to targeted next-generation sequencing (tNGS), which identified M. persicum and established the definitive diagnosis. After switching to an anti-M. persicum regimen, the pulmonary lesions gradually resolved, and the patient was cured. This case highlights that in immunocompromised individuals, M. persicum pulmonary disease closely mimics tuberculosis in both imaging and clinical presentation, and reliance solely on CT and sputum acid-fast staining readily leads to misdiagnosis. Molecular diagnostics are central to precise diagnosis and treatment, and this case offers a valuable clinical reference.