Background: Frequent COPD exacerbations are a major cause of hospital admission and mortality and are associated with increased airway inflammation. Macrolides have airway anti-inflammatory actions and may reduce the incidence of COPD exacerbations. Study Design: We performed a randomised double blind placebo controlled study of erythromycin 250 mg BD in COPD patients over 12 months, with primary outcome variable as the number of moderate and/or severe exacerbations (systemic steroid, antibiotic treated or hospitalised). Results: We randomised 109 outpatients; 69 (63%) males, 52 (48%) current smokers, mean (SD) age 67.2 (8.6) years, FEV1 1.32(0.53) l, FEV1% predicted 50(18) %, 38 (35%) of patients had 3 or more exacerbations in the year prior to recruitment with no differences between treatment groups. There were a total of 206 moderate to severe exacerbations: 125 occurred in the placebo arm. Withdrawals were 10 (placebo group) and 9 (macrolide group). Generalized linear modeling showed that the rate ratio for exacerbations in the macrolide-treated patients compared to placebo was 0.648 (95% CI: 0.489, 0.859), p = 0.003 and that these patients had shorter duration exacerbations, compared to placebo. There were no differences between macrolide and placebo arms in stable FEV1, sputum interleukin (IL)-6, IL-8, myeloperoxidase, bacterial flora, serum C-reactive protein or serum IL-6 or changes in these parameters from baseline to first exacerbation over the 1-year study period. Conclusions: Macrolide therapy was associated with a significant reduction in exacerbations compared to placebo and may be useful in decreasing the excessive disease burden in this important patient population. Clinical trials registry information available at: http://www.clinicaltrials.gov i.d. = NCT00147667