BACKGROUND: Respiratory virus infections are the most important trigger of respiratory illnesses in childhood. Data on the occurrence and the clinical impact of respiratory pathogens in the general population of infants are scarce. Therefore, we described the occurrence and clinical impact of respiratory pathogens in infants with respiratory tract infections during the first year of life. METHODS: In a prospective birth cohort study, infants were followed from birth through the first year of life with daily questionnaires about respiratory symptoms. Nose and throat swabs were collected during episodes with respiratory symptoms. Polymerase chain reaction was used to detect an extensive panel of respiratory pathogens. RESULTS: The parents reported a median of 5 respiratory episodes per infant per year. A total of 668 respiratory samples were collected in 305 infants. One or more respiratory pathogens were detected in 85% of the samples. The most common respiratory pathogens were human rhinovirus (HRV) (73% of the samples), respiratory syncytial virus (RSV) (11%), and coronavirus (8%). HRV infections were associated with a prolonged period of symptoms compared with RSV (P = 0.03). Infections with RSV were associated with more physician visits than HRV infections (P = 0.06). CONCLUSION: We found a high prevalence of respiratory pathogens among infants with parent-reported respiratory illnesses in the first year of life, with HRV being the most prevalent. Although RSV infections seemed to be responsible for the most severe symptoms compared with HRV, the overall burden of disease was highest for HRV infections.