To compare the efficacy and safety of the inhaled corticosteroid fluticasone propionate (FP) and the inhaled long-acting β2-agonist salmeterol (SM), when administered together in a single device (Diskus; GlaxoSmithKline, Inc; Research Triangle Park, NC), with that of placebo and the individual agents alone in patients with COPD. Randomized, double-blind, multicenter, placebo-controlled study. Seventy-six investigative sites in the United States. Seven hundred twenty-three patients ≥ 40 years of age with COPD and a mean baseline FEV1 of 42% predicted. FP (250 μg), SM (50 μg), FP plus SM combined in a single inhaler (FSC), or placebo administered twice daily through the Diskus device for 24 weeks. Primary efficacy measures were morning predose (ie, trough FEV1) for FSC compared with SM and 2-h postdose FEV1 for FSC compared with FP. Other efficacy measures were as follows: morning peak expiratory flow rate (PEF); transition dyspnea index; chronic respiratory disease questionnaire; chronic bronchitis symptom questionnaire; exacerbations; and other symptomatic measures. At Endpoint (ie, the last on-treatment, post-baseline assessment), treatment with FSC significantly (p ≤ 0.012) increased the morning predose FEV1 (165 mL) compared with SM (91 mL) and placebo (1 mL), and significantly (p ≤ 0.001) increased the 2-h postdose FEV1 (281 mL) compared with FP (147 mL) and placebo (58 mL). Improvements in lung function with FSC compared with FP and SM, and with FP and SM compared with placebo, as measured by the average daily morning PEF, was observed within approximately 24 h after the initiation of treatment, indicating an early onset of effect (p ≤ 0.034). Compared with placebo, FSC significantly improved dyspnea, quality of life, and symptoms of chronic bronchitis. The incidence of adverse effects (except for an increase in oral candidiasis with FSC and FP) were similar among the treatment groups. Treatment with FSC (FP, 250 μg, and SM, 50 μg) twice daily substantially improved morning lung function and sustained these improvements for over a period of 24 weeks compared with FP or SM treatment alone in patients with COPD, with no additional safety concerns for the combination treatment vs that with the individual components.