BACKGROUND: Immunocompromised patients with Lower Respiratory Tract Infections (LRTI) frequently encounter a diverse range of pathogenic infections, characterized by rapid disease progression and significant mortality rates due to reckless or excessive utilization of antibiotics. Therefore, it is crucial to promptly and accurately identify the causative microorganisms for pathogen diagnosis and clinical decision-making. The objective of this study is to evaluate the clinical applicability of metagenomic next-generation sequencing (mNGS) in the diagnosis and management of LRTI, as well as its impact on empirical antibacterial therapy for patients with varying immune statuses. METHODS: We conducted a comparative analysis of positivity rate, detection accuracy, pathogen spectrum, duration of treatment (DOT), and antibiotic management in a cohort of 283 patients diagnosed with lower respiratory tract infections. RESULTS: The positive detection rate was higher in mNGS compared to conventional culture in both immunocompetent group (89.92% vs. 28.57%, P <
0.001) and immunocompromised group (84.44% vs. 33.33%, P <
0.001). The antibiotic escalation in the immunocompromised group was more frequent than that in the immunocompetent group (49.00% vs. 31.00%, P = 0.018), but no difference was observed for antibiotic de-escalation (20.00% vs. 15.00%, P = 0.458). CONCLUSIONS: The application of mNGS can significantly enhance the pathogen detection rate and optimize antimicrobial drug management in immunocompromised patients with LRTI.