HIV-associated chronic lung disease (HCLD) is responsible for over half of all HIV-related deaths in children. Long-term treatment with the antibiotic azithromycin can reduce the frequency of acute respiratory episodes in HCLD, but it’s not clear exactly how. To find out, researchers recently investigated its effects on the respiratory microbiome in children and teens with HIV living in sub-Saharan Africa. They found that 48 weeks of once-weekly azithromycin treatment reduced the bacterial load in sputum (coughed-up saliva and mucus). Specifically, it reduced the abundances of HCLD-associated bacteria such as Haemophilus and Moraxella, and the reductions were still evident 24 weeks after the treatment was stopped. In addition, azithromycin stabilized the bacterial diversity in sputum, while the sputum of patients receiving a placebo drug exhibited reduced diversity. Notably, the decreased bacterial load and increased diversity in the azithromycin-treated group were correlated with improved lung function. Neisseria and Streptococcus bacteria were also positively associated with lung function, suggesting that they have a protective effect. Although species-level identification is needed, the findings help reveal how azithromycin prevents acute HCLD events in children and teens and suggest that modulating the airway microbiome is a promising strategy for HCLD treatment.