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RATIONALE The respiratory microbiota is increasingly being appreciated as an important mediator in the susceptibility to childhood respiratory tract infections (RTIs). Pathogens are presumed to originate from the nasopharyngeal ecosystem. OBJECTIVES To investigate the association between early-life respiratory microbiota and development of childhood RTIs. METHODS In a prospective birth cohort (Microbiome Utrecht Infant Study: MUIS), we characterized the oral microbiota longitudinally from birth until six months of age of 112 infants (9 regular samples/subject) and compared them with nasopharyngeal microbiota using 16S-rRNA-based sequencing. We also characterized oral and nasopharynx samples during RTI episodes in the first half year of life. MEASUREMENTS AND MAIN RESULTS Oral microbiota were driven mostly by feeding type, followed by age, mode of delivery and season of sampling. In contrast to our previously published associations between nasopharyngeal microbiota development and susceptibility to RTIs, oral microbiota development was not directly associated with susceptibility to RTI development. However, we did observe an influx of oral taxa, such as Neisseria lactamica, Streptococcus, Prevotella nanceiensis, Fusobacterium and Janthinobacterium lividum, in the nasopharyngeal microbiota prior to and during RTIs, which was accompanied by reduced presence and abundance of Corynebacterium, Dolosigranulum and Moraxella spp. Moreover, this phenomenon was accompanied by reduced niche differentiation indicating loss of ecological topography preceding confirmed RTIs. This loss of ecological topography was further augmented by start of daycare, and linked to consecutive development of symptomatic infections. CONCLUSIONS Together, our results link the loss of topography to subsequent development of RTI episodes. This may lead to new insights for prevention of RTIs and antibiotic utilization in childhood.