It is well established that macrolide antibiotics are efficacious in treating sinopulmonary infections in humans. However, a growing body of experimental and clinical evidence indicates that they also express distinct salutary effects that promote and sustain the reparative process in the chronically inflamed upper and lower respiratory tract. Unlike the anti-infective properties, these distinct effects are manifested at lower doses, usually after a relatively prolonged period (weeks) of treatment, and in the absence of an identifiable, viable pathogen. Long-term, low-dose administration of macrolide antibiotics has been used most commonly for sinusitis, diffuse panbronchiolitis, asthma, bronchiectasis, and cystic fibrosis. It is associated with down-regulation of nonspecific host inflammatory response to injury and promotion of tissue repair. Although large-scale trials are lacking, the prolonged use of these drugs has not been associated with emergence of clinically significant bacterial resistance or immunosuppression. Long-term, low-dose administration of 14- and 15-membered ring macrolide antibiotics may represent an important adjunct in the treatment of chronic inflammatory sinopulmonary diseases in humans.