There are few data and no convincing evidence to support the use of chronic oral antibiotic therapy in the adult CF population. However, therapy with macrolide antibiotics have garnered attention based on their effectiveness in the treatment of diffuse panbronchiolitis.50Promising preliminary observations suggested a clinical benefit in CF51–53 and led to several randomized, controlled clinical trials. A double-blind, placebo-controlled azithromycin trial in the United Kingdom54included 41 children, 20 of whom did not have persistent P aeruginosa infection. The crossover study design included two 6-month treatment phases and an intervening 2-month washout period. The median relative improvement in FEV1 in the azithromycin phase was 5.4%. Oral antibiotic use was reduced, but the number of pulmonary exacerbations and courses of IV antibiotics did not differ in the azithromycin and placebo phases. A 3-month randomized, placebo-controlled, double-blind trial of azithromycin enrolled 60 stable adults in Australia who were chronically infected with P aeruginosa.55 By chance, the treatment assignments resulted in significant differences between the azithromycin and placebo groups. At baseline, the placebo group contained more men, and on average the patients were taller, heavier, and had better lung function than those in the azithromycin group, requiring adjustments in their statistical analyses. Nevertheless, the azithromycin group had a 3.6% relative improvement in FEV1, had undergone fewer courses of IV antibiotic therapy, and had fewer hospital days. A 24-week, multicenter, randomized, placebo-controlled, double-blind trial of azithromycin56 in the United States enrolled 185 patients who were ≥ 6 years of age and were chronically infected with P aeruginosa. The azithromycin group experienced a 6.2% treatment benefit in relative FEV1 percent predicted change from baseline, decreased pulmonary exacerbations, decreased hospitalizations, and a 0.7-kg weight gain compared to the placebo group. The drug was well tolerated in all three trials. In summary, despite differences in patient populations, study design, and treatment regimens, all three trials demonstrated clinical improvement with azithromycin therapy. The mechanism of action remains to be elucidated. Based on this evidence, we believe that azithromycin should be considered for CF patients who are ≥ 6 years of age who are chronically infected with P aeruginosa. The US trial regimen was 500 mg thrice weekly for patients weighing ≥ 40 kg, and 250 mg thrice weekly for patients weighing 25 to 40 kg. A sputum smear and culture for acid-fast bacilli should be obtained prior to initiating chronic macrolide therapy because of the slight risk of having an undiagnosed nontuberculous mycobacterial infection developing macrolide resistance. For patients receiving chronic macrolide therapy, a smear and culture for acid-fast bacilli should be obtained every 6 months.