Macrolides are used primarily as antibiotics, but they may have other effects. This was first suggested after clinical experience showed that macrolides have an important therapeutic role some inflammatory airway diseases in which infection is not considered as an important etiologic factor. In vitro, ex vivo and in vivo experiments revealed that macrolides reinforce local defense mechanisms in the upper respiratory tract such as mucociliary clearance and epithelial impermeability. In addition, macrolides influence acute inflammation, by altering concentrations of cytokines and changing leucocyte functions. This paper aims to review the current knowledge on the non-antibiotic effects of macrolides on local defense mechanisms and acute inflammation in the upper respiratory tract.