Much controversy surrounds the use of β-agonists in obstructive lung disease. Regular β₂-agonist use in asthma results in tolerance to its effects and an increase in asthma-related deaths. Less is known about clinical outcomes in chronic obstructive pulmonary disease (COPD). This systematic review and meta-analysis evaluates the long-term effect of β₂-agonist use on severe exacebations requiring hospitalization or trial with drawal, respiratory deaths, and total mortality in patients with COPD. Results for β₂-agonists are compared with results for anticholinergics and inhaled corticosteroids. Pooled results from randomized controlled trials show that anticholinergics, such as tiotropium and ipratropium, significantly reduce severe exacerbations and respiratory deaths compared with placebo. Conversely, β₂-agonists increase respiratory deaths, probably because of tolerance that develops to their bronchodilator and bronchoprotective effects. Anticholinergics significantly reduce exacerbations and total mortality compared with β-agonists. The combination of the two bronchodilators is not more effective than anticholinergics alone in improving long-term clinical outcomes. Inhaled corticosteroids significantly reduce severe exacerbations and the decline in lung function over time, without affecting mortality. In conclusion, inhaled anticholinergic bronchodilators and corticosteroids should be used to improve long-term clinical outcomes in patients with COPD. β-Agonists increase respiratory deaths in COPD, possibly as a result of poorer disease control.