BackgroundBacteria colonizing the nasopharynx play a key role as gatekeepers of respiratory health. Yet, dynamics of early life nasopharyngeal (NP) bacterial profiles remain understudied in low- and middle-income countries (LMICs), where children have a high prevalence of risk factors for lower respiratory tract infection. We investigated longitudinal changes in NP bacterial profiles, and associated exposures, among healthy infants from low-income households in South Africa.MethodsWe used short fragment (V4 region) 16S rRNA gene amplicon sequencing to characterize NP bacterial profiles from 103 infants in a South African birth cohort, at monthly intervals from birth through the first 12 months of life and six monthly thereafter until 30 months.ResultsCorynebacteriumandStaphylococcuswere dominant colonizers at 1 month of life; however, these were rapidly replaced byMoraxella-orHaemophilus-dominated profiles by 4 months. This succession was almost universal and largely independent of a broad range of exposures. Warm weather (summer), lower gestational age, maternal smoking, no day-care attendance, antibiotic exposure, or low height-for-agezscore at 12 months were associated with higher alpha and beta diversity. Summer was also associated with higher relative abundances ofStaphylococcus,Streptococcus,Neisseria, or anaerobic gram-negative bacteria, whilst spring and winter were associated with higher relative abundances ofHaemophilusorCorynebacterium, respectively. Maternal smoking was associated with higher relative abundances ofPorphyromonas. Antibiotic therapy (or isoniazid prophylaxis for tuberculosis) was associated with higher relative abundance of anerobic taxa (Porphyromonas,Fusobacterium, andPrevotella) and with lower relative abundances of health associated-taxaCorynebacteriumandDolosigranulum. HIV-exposure was associated with higher relative abundances ofKlebsiellaorVeillonellaand lower relative abundances of an unclassified genus within the family Lachnospiraceae.ConclusionsIn this intensively sampled cohort, there was rapid and predictable replacement of early profiles dominated by health-associatedCorynebacteriumandDolosigranulumwith those dominated byMoraxellaandHaemophilus, independent of exposures. Season and antibiotic exposure were key determinants of NP bacterial profiles. Understudied but highly prevalent exposures prevalent in LMICs, including maternal smoking and HIV-exposure, were associated with NP bacterial profiles.Video AbstractSupplementary InformationThe online version contains supplementary material available at 10.1186/s40168-023-01563-5.