Respiratory syncytial virus (RSV) bronchiolitis is not only the leading cause of hospitalization in U.S. infants, but also a major risk factor for asthma development. While emerging evidence suggests clinical heterogeneity within RSV bronchiolitis, little is known about its biologically-distinct endotypes. Here, we integrated clinical, virus, airway microbiome (species-level), transcriptome, and metabolome data of 221 infants hospitalized with RSV bronchiolitis in a multicentre prospective cohort study. We identified four biologically- and clinically-meaningful endotypes: A) clinical(classic)microbiome(M. nonliquefaciens)inflammation(IFN-intermediate), B) clinical(atopic)microbiome(S. pneumoniae/M. catarrhalis)inflammation(IFN-high), C) clinical(severe)microbiome(mixed)inflammation(IFN-low), and D) clinical(non-atopic)microbiome(M.catarrhalis)inflammation(IL-6). Particularly, compared with endotype A infants, endotype B infants-who are characterized by a high proportion of IgE sensitization and rhinovirus coinfection, S. pneumoniae/M. catarrhalis codominance, and high IFN-alpha and -gamma response-had a significantly higher risk for developing asthma (9% vs. 38%; OR, 6.00: 95%CI, 2.08-21.9; P = 0.002). Our findings provide an evidence base for the early identification of high-risk children during a critical period of airway development.