Macrolides are known to possess immunomodulatory properties, next to their antimicrobial effects. These immunomodulatory activities have been proven beneficial in chronic pulmonary inflammatory diseases. Whether macrolides also exert favourable immunomodulatory effects during acute inflammation, and therefore can act as adjuvant therapy in community-acquired pneumonia (CAP), is less clear. We aimed to give an overview of the existing evidence from in vitro and in vivo studies on the immunomodulatory effects of macrolides during CAP. A comprehensive search in the PubMed/MEDLINE and Embase databases was performed. Two investigators independently examined the eligible literature. Studies that dealt with the effects of macrolides on the immune response, in terms of cytokine secretion and the number or function of inflammatory and structural cells during acute inflammation, were included. A total of 27 studies were included, of which 15 were in vitro studies, 9 in vivo, 2 both in vivo and in vitro, and 1 was in human subjects. Although the methods and experimental model systems used in these studies are very heterogeneous, macrolides in general tempered inflammation caused by viable and non-viable bacteria or their products. Cytokine secretion decreased, as did inflammatory and structural cell activation and histological inflammatory signs. Not all data, however, are consistent and sometimes pro-inflammatory effects were found. To conclude, the available literature suggests that macrolides can temper the inflammatory response during CAP, independent of their antimicrobial activity. However, because the studies differ in their methodology, no definite conclusions can be drawn.