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Background Antibiotic prescription for uncomplicated upper respiratory tract infection (URTI) in children is not recommended but remains common. The primary objective was to evaluate the relationship between antibiotic prescription for URTI prior to age 2 and antibiotic prescription for URTI after age 2. It was hypothesized that antibiotic prescription for URTI in early childhood may increase the risk of antibiotic use for subsequent URTIs. The secondary objective was to investigate whether this relationship was different for acute otitis media (AOM), for which antibiotics may be indicated. Methods A prospective cohort study was conducted between December 2008 and March 2016 at 9 primary care practices in Toronto, Canada. Healthy children aged 0–5 years that met TARGet Kids! cohort eligibility criteria were included if they had at least one sick visit prior to age 2 and least one sick visit after age 2. Generalized Estimating Equation (GEE) models were used to evaluate this relationship while considering within-subject correlation. Results Of 2380 participants followed for a mean duration of 4.6 years, children who received an antibiotic prescription for URTI prior to age 2 had higher odds of receiving an antibiotic prescription for URTI in later childhood (adjusted odds ratio: 1.39; 95% confidence interval: 1.19 to 1.63; P  < .001). This relationship did not appear to be different for AOM compared to non-AOM URTI. Conclusion Antibiotic prescription for URTI before age 2 was associated with antibiotic prescription for URTI in later childhood. Reducing early life antibiotic prescription for URTI may be associated with reduction in antibiotic prescription for subsequent URTIs. [ABSTRACT FROM AUTHOR]