Background: Current guidelines recommend the use of inhaled corticosteroids (ICSs) added to long-acting β2-agonists (LABAs) for treatment of symptomatic patients with severe and very severe COPD. However, the evidence has been inconclusive. The aim of this review was to assess the safety and efficacy of LABAs/ICSs compared with LABA monotherapy for patients with moderate-to-very severe COPD. Methods: Systematic searches were conducted on MEDLINE, EMBASE, the Cochrane Controlled Trials Register, and the trial registers of manufacturers, without language restriction. Primary outcomes were COPD exacerbations and mortality. Secondary outcomes included lung function, health-related quality of life, and adverse effects. Results: Eighteen randomized controlled trials (12,446 participants) were selected. Therapy with LABAs/ICSs did not decrease the number of severe exacerbations (relative risk [RR], 0.91; 95% CI, 0.82 to 1.01; I2 = 1%), or all-cause mortality (RR, 0.90; 95% CI, 0.76 to 1.06; I2 = 0%), respiratory mortality (RR, 0.80; 95% CI, 0.61 to 1.05; I2 = 0%), and cardiovascular mortality (RR, 1.22; 95% CI, 0.88 to 1.71; I2 = 0%). To the contrary, the number of moderate exacerbations (RR, 0.84; 95% CI, 0.74 to 0.96; I2 = 50%) and the St. George respiratory questionnaire total score (weighted mean difference, -1.88; 95% CI, -2.44 to -1.33; I2 = 29%) were significantly reduced with LABA/ICS therapy. Although therapy with LABAs/ICSs increases FEV1 significantly (0.06 and 0.04 L, respectively), they were associated with an increased risk of pneumonia (RR, 1.63; 95% CI, 1.35 to 1.98; I2 = 20%). Conclusions: Compared with LABA monotherapy, the magnitude of the benefits of LABA/ICS therapy did not reach that of the criteria for predefined clinically important effects and were associated with serious adverse effects. © 2009 American College of Chest Physicians.