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Background: Lower respiratory tract infections (LRTI) are a leading cause of critical illness and mortality in mechanically ventilated children; however, the pathogenic microbes frequently remain unknown. We combined traditional diagnostics with metagenomic next generation sequencing (mNGS) to evaluate the cause of LRTI in critically ill children., Methods: We conducted a prospective, multicentre cohort study of critically ill children aged 31 days to 17 years with respiratory failure requiring mechanical ventilation (>72 h) in the USA. By combining bacterial culture and upper respiratory viral PCR testing with mNGS of tracheal aspirate collected from all patients within 24 h of intubation, we determined the prevalence, age distribution, and seasonal variation of viral and bacterial respiratory pathogens detected by either method in children with or without LRTI., Findings: Between Feb 26, 2015, and Dec 31, 2017, of the 514 enrolled patients, 397 were eligible and included in the study (276 children with LRTI and 121 with no evidence of LRTI). A presumptive microbiological cause was identified in 255 (92%) children with LRTI, with respiratory syncytial virus (127 [46%]), Haemophilus influenzae (70 [25%]), and Moraxella catarrhalis (65 [24%]) being most prevalent. mNGS identified uncommon pathogens including Ureaplasma parvum and Bocavirus. Co-detection of viral and bacterial pathogens occurred in 144 (52%) patients. Incidental carriage of potentially pathogenic microbes occurred in 82 (68%) children without LRTI, with rhinovirus (30 [25%]) being most prevalent. Respiratory syncytial virus (p<0·0001), H influenzae (p=0·0006), and M catarrhalis (p=0·0002) were most common in children younger than 5 years. Viral and bacterial LRTI occurred predominantly during winter months., Interpretation: These findings demonstrate that respiratory syncytial virus, H influenzae, and M catarrhalis contribute disproportionately to severe paediatric LRTI, co-infections are common, and incidental carriage of potentially pathogenic microbes occurs frequently. Further, we provide a framework for future epidemiological and emerging pathogen surveillance studies, highlighting the potential for metagenomics to enhance clinical diagnosis., Funding: US National Institutes of Health and CZ Biohub., Competing Interests: Declaration of interests JK reports support from Genentech, outside the submitted work. LA reports funding from Pfizer, outside the submitted work. ABM reports grants from the Francis Family Foundation and the US National Institutes of Health (NIH) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), outside the submitted work. EAFS reports grants from the US NIH during the conduct of the study. EAFS reports grants, personal fees, and non-financial support from AstraZeneca, Merck, Regeneron, Pfizer, and Roche; personal fees, non-financial support, and other support from AbbVie; personal fees from Alere; other support from GSK; grants from Johnson and Johnson; and grants and non-financial support from Novavax, outside the submitted work. MWH reports grants from NIH NICHD, during the conduct of the study; and personal fees from La Jolla Pharmaceuticals, outside the submitted work. AFZ received NICHD funding through the Collaborative Pediatric Critical Care Research Network during the conduct of the study. KLM reports grants from NIH, during the conduct of the study. AS reports grants from NIH, outside the submitted work. MMP reports grants from NIH, during the conduct of the study. PSM reports grants from NIH NICHD, during the conduct of the study. JMD reports grants from NIH, during the conduct of the study. MSZ reports grants from National Heart, Lung, and Blood Institute (NHLBI; K23HL146936), outside the submitted work. PMM reports grants from NIH, during the conduct of the study. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)