Azithromycin, first synthesized in 1980, is a macrolide antibiotic related to erythromycin. It is widely used by the medical profession as a broad-spectrum antibiotic in the treatment of pneumonia, urinary tract infections and tonsillitis. In addition to its antibiotic properties, azithromycin has immune-modulating effects and is used for this reason in the management of cystic fibrosis and chronic obstructive pulmonary diseases. The drug is taken up by neutrophils, macrophages and fibroblasts, and is slowly released by these cells. Three diverse case reports are presented in which a single course of azithromycin (consisting of one 500 mg tablet being taken a day for three days) was prescribed before any periodontal intervention occurred. Azithromycin was the principal mode of treatment of severe chronic and aggressive periodontitis in Cases 1 and 2. Azithromycin, together with monthly subgingival debridement, was the treatment in Case 3 (severe chronic periodontitis in a poorly controlled diabetic complicated by gingival overgrowth related to medication with a calcium channel blocker). Favourable resolution of inflammation, reduction in pocket depths and evidence of bone regeneration were evident, even when no periodontal treatment had occurred. In Case 3, resolution of gingival overgrowth occurred over eight months. The potential implications for periodontal management, understanding of the pathogenesis of periodontal diseases and periodontal research are briefly discussed.