Introduction: Pulmonary infections are frequent in immunocompromised hosts (ICH), and microbial detection is difficult. As a new method, nextgeneration sequencing (NGS) may offer a solution.Objectives: This study aimed to assess the impact of NGS-assisted pathogenic detection on the diagnosis, treatment, and outcomes of ICH complicated by pulmonary infection and radiographic evidence of bilateral diffuse lesions.Methods: This study enrolled 356 patients with ICH complicated by pulmonary infection that were admitted to Zhongshan Hospital, Fudan University, from November 17, 2017, to November 23, 2018, including 102 and 254 in the NGS and non-NGS groups, respectively. Clinical characteristics, detection time, rough positive rate, effective positive rate, impact on anti-infective treatment plan, 30-day/60-day mortality, and in-hospital mortality were compared. Results: NGS-assisted pathogenic detection reduced detection time (28.2 h [interquartile range (IQR) 25.9-29.83 h] vs. 50.50 h [IQR 47.90-90.91 h], P < 0.001), increased positive rate, rate of mixed infection detected, effective positive rate, and proportion of antibiotic treatment modification (45.28% vs. 89.22%, 4.72% vs. 51.96%, 21.65% vs. 64.71%, 16.54% vs. 46.08%, P < 0.001). The NGS group had a significantly lower 60-day mortality rate (18.63% Donghui Zhang, Shujing Chen and Ying Wang contributed equally to this work.