Objectives/Hypothesis: Low-dose, long-term administration of macrolides (macrolide therapy) has been used as an effective treatment for chronic respiratory tract diseases. The authors reported on the nasopharyngeal flora in children treated with macrolide therapy. Study Design: Prospective study. Methods: Nasopharyngeal cultures were obtained from 73 children with chronic rhinosinusitis and/or otitis media with effusion at the end of the low-dose administration of clarithromycin (macrolide group). As control subjects, 98 children with chronic rhinosinusitis and/or otitis media with effusion who were not given macrolides were also included in the study. The culture results were evaluated with respect to antimicrobial susceptibility patterns, risk factors for carriage of erythromycin-resistant Streptococcus pneumoniae, and the clinical efficacy of the therapy. Results: The macrolide therapy did not have a significant effect on the incidence or the susceptibility patterns of potential pathogens except for Moraxella catarrhalis. Most of children in the macrolide group possessed a normal flora compared with the control children. The risk factors for carriage of erythromycin-resistant S pneumoniae were male gender in the macrolide group and age under 6 years and use of antimicrobial drugs other than macrolides in the control group. The clinical efficacy of the therapy was independent of carriage of erythromycin-resistant S pneumoniae. Conclusion: Macrolide therapy has little effect on carriage of drug-resistant pathogens, and the efficacy of the therapy depends on the anti-inflammatory effect of the drugs, which is independent of their antimicrobial effect.