There is, to date, no medical therapy that modifies the decline in lung function that occurs in COPD. As the disease becomes more severe, exacerbations of COPD become increasingly common, affecting patient quality of life and increasing health care costs. Mucolytic agents, through their actions on inflammatory and oxidative pathways, have potential benefits in COPD. This paper reviews the randomized controlled trial (RCT) evidence for the effectiveness of at least 2 months of daily therapy with oral mucolytics in COPD. Based on evidence from 26 RCTs, mucolytics reduce exacerbations by up to 0.8 exacerbations per year, with a greater effect in patients with more severe COPD. This effect appears to be of a similar magnitude to the reduction in exacerbations seen with tiotropium and inhaled corticosteroids (ICS), but RCTs that compared the agents would be required to confirm this. Mucolytics do not affect the rate of lung function decline, but they do not have any significant adverse effects. Mucolytic treatment should be considered in: patients with more severe COPD who have frequent or prolonged exacerbations; those who are repeatedly admitted to hospital; or in those patients with frequent exacerbations who are unable to take tiotropium or ICS.