Background: Previous studies in which molecular-based techniques have been used to identify the causative pathogens of respiratory tract infection have investigated hospitalized children only. We report a prospective study designed to determine the frequency and clinical presentation of community-acquired respiratory illness in infancy associated with 8 common respiratory pathogens. Methods: Eighty-eight infants were monitored through their first winter. With each respiratory illness, infants were examined, and a nasal lavage specimen was collected. Individual reverse transcription-polymerase chain reactions were performed to detect infection with picornaviruses (rhinoviruses and enteroviruses), coronaviruses (serotypes OC43 and 229E), adenoviruses, parainfluenza viruses 1-3, influenza viruses (types A and 13), respiratory syncytial virus (RSV), Chlamyclia pneumoniae and Mycoplasma pneumoniae. Results: Picomaviruses were the most frequently detected pathogen identified in 46% (56 of 123) of episodes, followed by RSV (27%), parainfluenza viruses (13%) and coronaviruses (9%). Dual pathogen infections were identified in 20% of episodes, predominantly caused by picornaviruses together with either RSV or parainfluenza viruses. RSV infection was significantly associated with a diagnosis of bronchiolitis. No other associations were found between pathogen and clinical diagnosis. Dual infection did not predispose infants to a more severe clinical course. Conclusions: Picomaviruses are the predominant cause of community-acquired respiratory tract infection in the first year of life. Large prospective community-based studies will be needed to fully evaluate the contribution of picomaviruses, both in isolation and in combination with other respiratory pathogens, to the various clinical syndromes of respiratory infection observed during infancy.