To analyze systemic inflammation in neonates in which Moraxella catarrhalis, Haemophilus influenza, and/or Streptococcus pneumoniae colonized in the upper airways.Neonates from 2 ongoing clinical mother-child cohorts from Zealand, Denmark, were included. The high-risk cohort, COPSAC2000, included 411 children of mothers with asthma. COPSAC2010 is a population-based cohort that enrolled 700 children.Airway aspirates were sampled and nasopharyngeal swabs were collected in asymptomatic neonates at the age of 1 month from the at-risk cohort. Airway aspirates were collected at 1 and 3 months in the population-based cohort. Aspirates were cultured and quantified by polymerase chain reaction for identification of M catarrhalis, H influenza, and S pneumoniae. At the age of 6 months, plasma levels of C-reactive protein, tumor necrosis factor α, and interleukin-6 were measured to study systemic inflammation.Bacterial colonization was associated with increased levels of C-reactive protein in both cohorts. Children colonized with M catarrhalis, H influenza, and/or S pneumoniae in the hypopharynx were found to have a systemic inflammatory profile when compared with noncolonized children.The researchers found that low-grade systemic inflammation is present in the hypopharynx of asymptomatic neonates colonized with M catarrhalis, H influenza, and/or S pneumoniae.The researchers in this study confirm the relationship between neonatal bacterial upper airway colonization and low-grade systemic inflammation in both an at-risk cohort and a population-based cohort. These findings further implicate the influence of the microbiome on the development of childhood asthma, a disease associated with systemic low-grade inflammation. Future researchers could provide information regarding whether interventions to eradicate colonization of the hypopharynx of neonates would prove beneficial in the potential prevention of the development of atopic disease in childhood.