Respiratory disease is important in horses, particularly in young Thoroughbred racehorses, and inflammation that is detected in the trachea and bronchi (termed inflammatory airway disease [IAD]) is more significant in this population in terms of impact and frequency than other presentations of respiratory disease. IAD, which is characterized by neutrophilic inflammation, mild clinical signs, and accumulation of mucus in the trachea, may be multifactorial, possibly involving infections and environmental and immunological factors, and its etiology remains unclear. This 3-year longitudinal study of young Thoroughbred racehorses was undertaken to characterize the associations of IAD and nasal discharge with viral and bacterial infections. IAD was statistically associated with tracheal infection with Streptococcus pneumoniae (capsule type 3), Streptococcus zooepidemicus, Actinobacillus spp., and Mycoplasma equirhinis and equine herpesvirus 1 and 4 infections, after adjustment for variation between training yards, seasons, and age groups. The association with S. pneumoniae and S. zooepidemicus was independent of prior viral infection and, critically, was dependent on the numbers of organisms isolated. S. pneumoniae was significant only in horses that were 2 years old or younger. The prevalence and incidence of IAD, S. zooepidemicus, and S. pneumoniae decreased in parallel with age, consistent with increased disease resistance, perhaps by the acquisition of immunity. The study provided evidence for S. zooepidemicus and S. pneumoniae playing an important etiological role in the pathogenesis of IAD in young horses.