BACKGROUND: Following evidence from randomized controlled trials, patients with bronchiectasis unrelated to cystic fibrosis (CF) receive long-term azithromycin to reduce acute respiratory exacerbations. However, the period when azithromycin is effective and those likely to most benefit remains unknown. RESEARCH QUESTIONS: (i) What is the period following its commencement when azithromycin is most effective? and (ii) What factors may modify azithromycin effects? STUDY DESIGN AND METHODS: A secondary analysis was conducted of our previous randomized controlled trial involving 89 Indigenous children with bronchiectasis unrelated to CF. Semi-parametric poisson regression identified the azithromycin efficacy period. Multivariable poisson regression identified factors that modify azithromycin effect. RESULTS: Azithromycin was associated with fewer exacerbations per child-week during weeks 4-96, with the most effective period observed between weeks 17-62. Eleven factors were associated with different azithromycin effects, four of them were significant at p<0.05 level. Compared with their counterparts, higher reduction in excerbations was observed in: children with nasopharyngeal carriage of bacterial pathogens, [incidence rate ratio, IRR=0.81 (95% confidence interval 0.57 to 1.14) versus 0.29 (0.20 to 0.44), p<0.001]; New Zealand children [IRR=0.73 (0.51 to 1.03) versus 0.39 (0.28 to 0.55), p=0.012]; and those with higher weight-for-height z-scores [interaction IRR=0.82 (0.67 to 0.99), p=0.044]. Compared with their counterparts, lower reduction was observed in those born preterm [IRR=0.41 (0.30 to 0.55) versus 0.74 (0.49 to 1.10), p=0.012]. INTERPRETATION: Regular azithromycin is best used for at least 17-weeks and up to 62-weeks as these periods provide maximum benefit for Indigenous children with bronchiectasis unrelated to CF. Several factors modified azithromycin benefits, however these traits need confirmation in larger studies before being adopted into clinical practice.