Rationale: Infections with viral and bacterial pathogens in the first year of life have been implicated in the development of chronic respiratory disease, but the interplay between viruses, bacteria and host is complex, and underlying mechanisms remain largely unknown.Objectives: To prospectively determine whether the nasal microbiota changes between the onset of the first symptomatic acute respiratory tract infection (ARI) in the first year of life and three weeks later, and to explore possible associations of the nasal microbiota with host, environmental and viral factors, as well as with duration of respiratory symptoms.Methods: Nasal microbiota profiles of 163 infants in their first year of life were determined at the onset of the first ARI, and three weeks later, by 16S ribosomal ribonucleic acid PCR amplification and subsequent pyrosequencing. Patients were clustered based on their nasal microbiota using hierarchical clustering methods at both time points.Measurements and Main Results: We identified five dominant infant clusters with distinct microbiota at the onset of ARI in symptomatic formerly infection-naïve infants; these five clusters reduced to only three clusters after three weeks. In these three clusters, symptom persistence was overrepresented in the Streptococcaceae-dominated cluster and underrepresented in the cluster dominated by “Others” (P < 0.001). Duration of symptoms was not associated with type of respiratory virus.Conclusions: Infants with prolonged respiratory symptoms after their first ARI tend to exhibit distinct microbial compositions at the onset, and three weeks later, consistent with a modulatory effect of the microbiota on the inflammatory response.