Rationale: Inhaled corticosteroids have been shown to decrease exacerbations in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Their effects in patients with milder airflow obstruction remain unclear. Objectives: This was an analysis of exacerbations in the SUMMIT (Study to Understand Mortality and Morbidity) study. Methods: In a double-blind, randomized controlled trial, once-daily inhaled placebo, fluticasone furoate (FF; 100 mg), vilanterol (VI; 25 mg), or the combination of FF/VI was administered. The primary outcome was all-cause mortality. Exacerbations of COPD were an additional predefined endpoint. A total of 1,368 centers in 43 countries and 16,485 patients with moderate COPD and heightened cardiovascular risk were included in the study. Measurements and Main Results: Compared with placebo, FF/VI reduced the rate of moderate and/or severe exacerbations by 29% (95% confidence interval [CI], 22-35; P , 0.001) and the rate of hospitalized exacerbations by 27% (95% CI, 13-39; P , 0.001). These relative effects were similar regardless of whether subjects had a history of exacerbation in the year before the study or an FEV1 ,60% or >60% of predicted. The number needed to treat was not influenced by baseline FEV1 but was influenced by the history of exacerbations. FF/VI also reduced the rate of exacerbations treated with corticosteroids alone or with corticosteroids and antibiotics but not the rates of those treated with antibiotics alone. Conclusions: Patients with moderate chronic airflow obstruction experienced a reduction in exacerbations with FF/VI compared with placebo, irrespective of a history of exacerbations or baseline FEV1. Clinical trial registered with www.clinicaltrials.gov (NCT 01313676; GSK Study number 113782).