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Background: High bacterial burden in the lung microbiota predicts progression of idiopathic pulmonary fibrosis (IPF). Azithromycin (AZT) is a macrolide antibiotic known to alter the lung microbiota in several chronic pulmonary diseases, and observational studies have shown a positive effect of AZT on mortality and hospitalisation rate in IPF. However, the effect of AZT on the lung microbiota in IPF remains unknown., Methods: We sought to determine the impact of a 3-month course of AZT on the lung microbiota in IPF. We assessed sputum and oropharyngeal swab specimens from 24 adults with IPF included in a randomised controlled crossover trial of oral AZT 500 mg 3 times per week. 16S rRNA gene amplicon sequencing and quantitative PCR (qPCR) were performed to assess bacterial communities. Antibiotic resistance genes (ARGs) were assessed using real-time qPCR., Results: AZT significantly decreased community diversity with a stronger and more persistent effect in the lower airways (sputum). AZT treatment altered the temporal kinetics of the upper (oropharyngeal swab) and lower airway microbiota, increasing community similarity between the two sites for 1 month after macrolide cessation. Patients with an increase in ARG carriage had lower bacterial density and enrichment of the genus Streptococcus . In contrast, patients with more stable ARG carriage had higher bacterial density and enrichment in Prevotella ., Conclusions: AZT caused sustained changes in the diversity and composition of the upper and lower airway microbiota in IPF, with effects on the temporal and spatial dynamics between the two sites., Competing Interests: Conflict of interest: C.F. Clarenbach reports consulting fees from GSK, Novartis, Vifo, Boehringer, AstraZeneca, Sanofi and Daiichi Sankyo, outside the submitted work; payment or honoraria from GSK, Novartis, Vifor, Boehringer, AstraZeneca and Sanofi, outside the submitted work; support for attending meetings and/or travel from Boehringer and AstraZeneca, outside the submitted work. S.A. Guler reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from MSD, Boehringer Ingelheim and Roche, outside the submitted work. M. Funke-Chambour reports support for the present manuscript from the Research Fund of the Swiss Lung Association, Bern; grants or contracts from Boehringer Ingelheim, Roche and CSL Behring, outside the submitted work; consulting fees from Boehringer Ingelheim and Daiichi Sankyo, outside the submitted work; payment or honoraria from MSD and Novartis, outside the submitted work. C. von Garnier reports grants or contracts from Ligue Pulmonaire Vaudoise, Fondation Juchum and Fondation Placide Nicod, outside the submitted work. The remaining authors have nothing to disclose., (Copyright ©The authors 2023.)