Long-term treatment with macrolides has recently been shown to reduce COPD exacerbations in doses lower than bactericidal doses. This article aims to critically review the international literature relating to the long-term effectiveness and safety of macrolides and to estimate the budget impact of preventing exacerbations with azithromycin in Belgium. Controlled clinical studies focusing on the prevention of COPD exacerbations with long-term macrolide treatment were identified in PubMed, EMBASE, Controlled Trials Registry of the Cochrane Library, and Social Science and Citation Index. The budget impact of preventing exacerbations with azithromycin in Belgium over a one-year period was calculated as the difference between the additional expenditure of annual treatment with azithromycin and the savings in hospital expenditure arising from fewer COPD exacerbations in patients with GOLD stages II–IV. Prevalence and resource use data were derived from the literature and unit cost data from Belgian sources. The literature review suggests that long-term treatment of COPD patients with azithromycin, erythromycin or clarithromycin is effective and safe, and reduces exacerbations and related hospitalizations. However, uncertainty remains about the specific patient population that is most likely to benefit from long-term macrolide treatment, the optimal dose and duration of macrolide treatment, and the potential impact of long-term macrolide treatment on resistance. The budget impact analysis demonstrated that annual hospital savings of €950 million resulting from fewer exacerbations outweighed additional expenditure on azithromycin of €595 million, implying that the prevention of COPD exacerbations with azithromycin is a cost saving strategy in Belgium.