Copyright © 2015 by the American Thoracic Society Rationale: Radiographically confirmed pneumonia risk with inhaled corticosteroid use in chronic obstructive pulmonary disease (COPD) has not been assessed to date. Objectives: To determine the incidence of pneumonia, risk factors, and clinical attributes with inhaled fluticasone furoate (FF) in patients with COPD with an exacerbation history. Methods: Two replicate, 1-year, double-blind clinical trials enrolled subjects with COPD with moderate to very severe airflow limitation and at least one exacerbation within the prior year. Subjects were randomized 1:1:1:1 to receive inhaled once-daily vilanterol (VI) 25 μg or VI 25 μg combined with 50, 100, or 200 μg FF. Subjects were required to have a chest radiograph at screening and within 48 hours of any suspected pneumonia or exacerbation. Measurements and Main Results: Among 3,255 randomized subjects, 205 pneumonia events occurred in 181 subjects. Chest imaging was available for 195 (95%) of these events. Chest radiographs were also obtained for 1,793 (70%) of the 2,545 moderate and severe exacerbations. For VI alone and the combination with 50, 100, or 200 μg FF, reported pneumonia incidence was 3, 6, 6, and 7%, respectively. However, for events with compatible parenchymal infiltrates, the respective incidences were 2, 4, 4, and 5%. Factors associated with at least a twofold increase in the risk of pneumonia with FF/VI treatment were being a current smoker, having prior pneumonia, body mass index <25 kg/m2, and severe airflow limitation. Conclusions: Radiographically confirmed pneumonia risk is increased with inhaled FF/VI, although at less than investigator-defined rates. Modifiable pneumonia risk factors should be considered when attempting to optimize COPD management.