Long-term treatment of airway inflammation/infection with macrolide antibiotics has now been in use for almost 30 years. Whereas the beneficial clinical effect in cystic fibrosis and COPD have been backed up by randomized controlled trials, the evidence from the upper airways is not as strong. We have identified 22 open studies in chronic rhinosinusitis, with and without polyps, but only 2 randomized controlled trials. Of the controlled trials, the one including CRS patients just without polyps, showed a significant effect in sino-nasal outcome test, saccharine transit time, nasal endoscopy, and IL-8 levels in lavage fluid after 12 weeks of roxithromycin, whereas, in the other RCT with a mixed study group of CRS patients with and without polyps, 12 weeks of azithromycin showed no effect compared to placebo. Concerns regarding the risk of macrolides to induce arrhythmia have been raised. Recent FDA guidelines changes has recommended caution in patients with risk factors such as long QT syndrome, bradycardia, hypokalemia, or hypomagnesemia. Ototoxicity is another concern. Long-term macrolide antibiotics in the treatment of CRS patients is still a viable option in a select group of patients.