Background <p>This study aimed to evaluate the diagnostic utility of metagenomic next-generation sequencing (mNGS) in detecting pulmonary infections in persons living with HIV(PLWH).</p> Methods <p>We conducted a retrospective study involving 246 PLWH with pulmonary infections. Bronchoalveolar lavage fluid (BALF) specimens were collected from all patients. mNGS and traditional microbial cultures were performed in parallel to compare the differences in pathogen identification. Patients were stratified by immune status based on CD4⁺ T cell counts, and the association between pathogen profiles and immunodeficiency severity was analyzed.</p> Results <p>mNGS demonstrated a significantly higher pathogen detection sensitivity (98.0%) compared to traditional cultures (32.1%). The spectrum of pathogens detected by mNGS and culture methods differed significantly. mNGS identified 123 pathogenic microorganisms, whereas cultures detected only 17. mNGS detected additional pathogens, including viruses (e.g., Epstein-Barr virus and cytomegalovirus) and fastidious microorganisms (e.g., <i>Pneumocystis jirovecii</i>). Furthermore, mNGS revealed a significant correlation between PLWH-associated immunodeficiency and pathogen profiles. The diversity of pathogens, particularly fungi and viruses, increased with declining CD4⁺ T cell counts (<i>p</i> &lt; 0.05).</p> Conclusion <p>mNGS comprehensively characterizes the complex pathogen spectrum in PLWH-associated pulmonary infections, significantly enhancing detection sensitivity for mixed and fastidious infections, thereby guiding targeted anti-infective therapy. Immunosuppression severity strongly correlates with opportunistic pathogen profiles and the risk of specific pathogen detection, highlighting the importance of immune status-guided clinical strategies. mNGS serves as a valuable adjunct to conventional diagnostic methods, enhancing the detection and prognostic assessment of infectious complications in PLWH.</p>