Background Asthma is a highly prevalent chronic lung disease that commonly originates in early childhood. Colonization of neonatal airways with the pathogenic bacterial strains Haemophilus influenzae , Moraxella catarrhalis , and Streptococcus pneumoniae is associated with increased risk of later childhood asthma. We hypothesized that children with asthma have an abnormal immune response to pathogenic bacteria in infancy. Objective We aimed to assess the bacterial immune response in asymptomatic infants and the association with later development of asthma by age 7 years. Methods The Copenhagen Prospective Studies on Asthma in Childhood birth cohort was followed prospectively, and asthma was diagnosed at age 7 years. The immune response to H influenzae , M catarrhalis , and S pneumoniae was analyzed in 292 infants using PBMCs isolated and stored since the age of 6 months. The immune response was assessed based on the pattern of cytokines produced and T-cell activation. Results The immune response to pathogenic bacteria was different in infants with asthma by 7 years of age ( P  = .0007). In particular, prospective asthmatic subjects had aberrant production of IL-5 ( P  = .008), IL-13 ( P  = .057), IL-17 ( P  = .001), and IL-10 ( P  = .028), whereas there were no differences in T-cell activation or peripheral T-cell composition. Conclusions Children with asthma by school age exhibited an aberrant immune response to pathogenic bacteria in infancy. We propose that an abnormal immune response to pathogenic bacteria colonizing the airways in early life might lead to chronic airway inflammation and childhood asthma.